TW517049B - Phenyl-and aminophenyl-alkylsulfonamide and urea derivatives, their process for preparation and pharmaceutical composition containing the same, and intermediate compounds therefor - Google Patents

Abstract

The present invention concerns novel compounds represented by the Formula: wherein: A is R1q(R3R60N)m(Z)(NR2)n; m and q are each 0 or 1, with the proviso that when q is 1, m is 0 and when q is 0, m is 1; Z is C=O or SO 2; n is 1 with the proviso that, when Z is C=O, m is 1; X is -NH-, -CH2-, or -OCH2-; Y is 2-imidazoline, 2-oxazoline, 2-thiazoline, or 4-imidazole; R 1 is H, lower alkyl, or phenyl, with the proviso that, when R1 is H, m is 1; R2, R3, R60 are each independently H, lower alkyl, or phenyl; R4, R5, R6, and R7 are each independently hydrogen, lower alkyl, -CF3, lower alkoxy, halogen, phenyl, lower alkeny, hydroxyl, lower alkylsulfonamido, or lower cycloalkyl, wherein R2 and R7 optionally may be taken together to form alkylene or alkenylene of 2 to 3 atoms in an unsubstituted or optionally substituted 5-or 6-membered ring, wherein the optional substituents on the ring are halo, lower alkyl, or -CN, with the proviso that, when R7 is hydroxyl or lower alkylsulfonamido, then X is not -NH- when Y is 2-imidazoline. The compounds include pharmaceutically acceptable salts of the above. In the above formula A may be, for example, (R1SO2NR2-), (R3R60NSO2NR2-), or (R3R60NCONR2-). The invention also includes the use of the above compounds, and compositions containing them, as alpha 1A/1L agonists in the treatment of various disease states such as urinary incontinence, nasal congestion, priapism, depression, anxiety, dementia, senility, Alzheimer's, deficiencies in attentiveness and cognition, and eating disorders such as obesity, bulimia, and anorexia.

Description

Printed by the Consumer Standards Coordinator of the Central Standards Bureau of the Ministry of Labor of the People's Republic of China 517049 A7 _____________ B7 V. Description of the Invention (1) The present invention relates to methylphenyl, methoxybenzyl, and aminophenylalkyl razylamine and urea. A variety of 2-Mi Junlin, 2-Zi Junlin, 2-Yao Junlin and 4-Mi Jun derivatives, and their use in the treatment of various food disease states such as urinary incontinence, nasal congestion, abnormal erections, depression, Anxiety, dementia, aging, Alzheimer's disease, lack of attention and discrimination, and use of eating disorders such as obesity, bulimia, and anorexia. Urinary incontinence The lower urethra is composed of the bladder and urinary urinary tract. Under normal urinary and urinary function requires ataxia of the bladder (urinary muscle) and increased urethral smooth muscle tension when the bladder is full. In contrast, urinary excretion (urination) requires ataxia of urinary muscles and relaxation of urethral smooth muscles. This ataxia is achieved by amalgamation of afferent (sensory) and efferent (parasympathetic, sympathetic, and physical) neural activities in the medial and peripheral nerve centers. Incontinence is a condition characterized by visual confirmation of involuntary loss of urine. It becomes a social and health issue. In short, urinary incontinence is caused by the inability of the bladder and / or urinary tract to function properly, or when the mutual aid of their functions is lacking. It is estimated that at least 10 million Americans suffer from urinary incontinence. However, the prevalence of urinary incontinence is twice as high among women, and it is highest among menopause women, and it is also true among men. Urinary incontinence can be classified into four basic types. Rush incontinence (detrusor instability) is the involuntary loss of urine associated with intense oppression. This type of incontinence is the result of excessively active or overly sensitive detrusor muscles. Patients with excessive activity of the detrusor muscle will experience inappropriate compression of the depressor's muscle and increase the internal pressure of the upper arm when the upper arm is full. From excessive -4- This paper size applies Chinese National Standard (cNS) A4 specification (210x297 mm) (Please read the precautions on the back before filling this page)

517049 A7 B7 V. Description of the invention (2) Instability of detrusor muscle caused by sensitive detrusor muscles (excessive reflex detrusor muscle reflex), often related to neurological disorders.眞 Positive depressive incontinence (incomplete outlet closure) is an involuntary loss of urine that occurs when the pressure in the bladder rises due to increased intra-abdominal pressure and exceeds the resistance performed by the urethral closure mechanism. Incidents of depressive incontinence may be due to normal activity ' such as laughing, coughing, snoring, exercise, or (in patients with severe depressive incontinence) standing or walking. Physiologically, depressive incontinence is often characterized by bladder neck droop and bladder outlet injection. This type of incontinence is most common in pregnant women because pregnancy and vaginal delivery can result in loss of urinary bladder angle and damage to external sphincter. The hormonal changes associated with menstrual periods may worsen the condition. Overflow incontinence is an involuntary loss of urine caused by a weakening of the detrusor muscle or by the failure of the detrusor muscle to transmit the proper message (sensory) when the bladder is full. Sporadic episodes of incontinence are characterized by frequent or persistent urine drips and incomplete or unsuccessful discharge. Functional incontinence, as opposed to the above types of incontinence, is defined by the basic physiological dysfunction of the bladder or urinary diarrhea. This type of incontinence includes prints such as reduced mobility, taking medications (such as diuretics, toxins, or avar) _ adrenaline is printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (read the precautions on the back before completing this (P.) Body antagonists), or mental problems such as depression, and involuntary loss of urine. The treatment of incontinence depends on its type and severity. Of the four types of incontinence, medical therapy is most effective for urgent incontinence. Various pharmaceutical agents such as anticholinergic drugs, smooth muscle relaxants, calcium channel antagonists, and beta-adrenergic receptor activators are used to reduce the contractility of the bladder. Some patients seem to benefit from 1____ 冬 __ This paper size applies the Chinese National Standard (CNS) A4 specification (210 ^ 297 mm―) ^ ------- 517049 A7 B7 V. Description of the invention (3) Taking female Hormones (menopausal women) and atorvastatin receptor agonists. However (please read the notes on the back before filling this page) ’These drugs are most likely to act on the urethral level to increase closing pressure and prevent urine loss. Mild to moderate depressive incontinence can be treated pharmacologically or by conservative methods such as physical therapy (Kegel's drill) and functional electronic stimulation, both of which are aimed at strengthening the urinary diaphragmatic muscles. Surgery is indicated for patients with severe depressive incontinence. Surgical techniques work to improve the proper alignment of the bladder, urethra, and surrounding structures. Only a limited number of medicinal agents for the treatment of depressive incontinence have been developed, and their success rates have varied considerably. In menopausal women, estrogen replacement therapy is thought to improve incontinence by increasing urethral closure pressure by increasing urethral length and muscle thickness. Estrogen can also increase the expression of adrenaline receptors in the urinary tract (Wein, North American Clinical Urology 995) 22: 557-5 77). The efficacy of estrogen therapy is not universally accepted worldwide. Phenylpropanolamine and pseudoephedrine printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs are considered to be the first-line therapy for mild to moderate depressive incontinence (Wein; Lu Debo, previously mentioned) Lundberg (eds.), JAMA 1989) Ml (18): 2685-2690). These agents are believed to act by directly activating the avalin adrenaline receptor and indirectly by displacing endogenous norepinephrine from sympathetic neurons and subsequently absorbing them into nerve endings (Anderson ( Andersson) and Sjogren (Progress in Neurology (98211 9: 7 1-89). Activation of avar i-adrenergic receptors on smooth muscle cells of the proximal urinary urinary bladder and bladder neck (Solad ( Sourander), Geriatrics (1990) 19_26; the aforementioned Wein) will cause contraction and increase the pressure of urethral closure. -6- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 5l7 〇49 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (4) The use of phenylpropanolamine and pseudoephedrine is limited, and it is lacking in the subtype of avar 1-adrenaline receptor. Selectivity, and the indirect effects of these agents (that is, activation of avar 1 _, avar r and beta-adrenergic receptors located in the central nervous system and the periphery). As a result, any desired of these agents Treatment is weak and may be accompanied by undesired Side effects such as increased blood pressure. Increased blood pressure is dose-dependent and therefore limits its ability to reach therapeutically effective circulating concentrations of these agents (mentioned previously, Anderssdn and Sjogren). Also, in In some patients; these agents can cause insomnia, anxiety, and dizziness due to their stimulating effects on the central nervous system (mentioned previously, Andersson and Sjogren; previously mentioned, Wein )) 〇 Methionine is a sympathomimetic agent that has been evaluated for the treatment of depressive incontinence. This Avar ^ adrenergic receptor activator is converted into active phenylethylamine (ST- 105 9) Prodrugs. The clinical efficacy of methamphetamine has been decisively confirmed (the aforementioned, Anderssoil and Sjogren). Similar to the compounds mentioned above, their beneficial effects may be limited by The cross-reactivity of other adrenergic receptors may limit the maximum achievable dose. Understanding the subtypes of avar adrenaline receptors and their participation in various physiological processes can help develop Exhibited more effective drugs for treating depression and possibly urge incontinence. Avarang epinephrine receptor system is a special neuroreceptor protein located in the peripheral and central nervous system and located on tissues of the whole body. The body is an important converter that controls many physiological functions, and therefore represents an important target for drug development. The drugs that interact at these receptors include two main categories: stimulants _ -7- This paper is compliant with national standards ( CNS) Α4 specification (210X297 mm) C Read the precautions on the back before filling in this page)

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Distillation 517049 A7 —--- ~~~~ _ V. Description of the invention (5) Motile agents, which are equivalent to the ability to activate the adrenergic receptor, mimic endogenous ligands ( Norepinephrine, epinephrine, and antagonists are used to block the action of endogenous ligands. A Over the past 15 years, it has been shown that the avalanine-adrenaline receptor and the standard avalanine-adrenaline receptor A more accurate understanding of the body's pharmaceuticals. In 1977, 'only one type of avar-adrenaline receptor was known to exist. Between 1977 and 1986, it was accepted by the Scientific Association and exists in the middle frame and the toilet nervous system. At least two kinds of avar adrenaline receptors, avarcan and avar 2_. The new technology has enabled Zhongzu to be widely distributed in the central and peripheral nervous systems, with significantly different adrenaline receptor proteins. Currently there are three The human advaline adrenaline receptor has been lightly colonized (Ava 1A, Ava 1B, and Ava iD), and its expression and pharmacological characterization (Hieble et al., Tomb 1995) ϋ: 267 -270). The name of adrenaline receptors without Avar 1C is due to the origin of the subclass of adrenaline receptors. In 1990, an adrenaline receptor was selected and named as avalic- Adrenergic receptors, but the mRNA of this selected strain cannot be detected in animal tissues with known performance and pharmacologically determined avaria adrenaline receptors (Ford (Forz et al., Pharmacology Trends in Science (1994) ^ 5: 167-170) 〇 The fourth class (Ava 1L_adrenergic receptor) has been described pharmacologically, but no significant different gene products have been found (Flahan ( F 丨 avahan) and Vahnoutte, Trends in Pharmacology (1986) 7: 347-349; Muramatsu et al., Br · J Pharmacol · (1990, 99: 197-201). Regardless of Aval ία-adrenergic receptor mRNA in the low urethral weave -8 _ This paper size applies to Chinese National Standard (CNS) A4 specifications ϋ〇 × 297 mm) " (Please read the precautions on the back before filling this page )

517049 V. Description of the invention (6 Dominance, which is also pharmacologically determined to be related to Ava ", the adrenaline receptor mediated by Ava ... the fingerprint structure of the antagonist of the adrenaline receptor that is most relevant to low urethral smooth muscle contraction ,, (Ford et al., Molecular Pharmacology 1996) — 209 215). Recently, this apparent difference has been lightly observed while studying the functional response in cells transfected with selected favar a Α-adrenergic receptors. / Compared to radioligand studies traditionally performed in hypertonic buffers at sub-physiological temperatures, functional studies in transfected cells have been performed in physiological buffers at physiological temperatures. With these conditions, the pharmacology of the key antagonists is very similar to that of Aval-1L-adrenoceptor (Ford et al., Br ^ Marma ^ c ^ (1990) 99: 197-201). Therefore, it appears that the selected ovarian adrenaline receptors can exhibit two different pharmacology (Ava 1A- and Ava 1L_), depending on the experimental conditions used. It should be noted that this phenomenon is specific to the subtype of avar ia-adrenaline receptors, and does not change the pharmacology of the selected azovata- or advaline 1D-adrenaline receptors due to changes in experimental conditions in similar methods. (The aforementioned Ford et al.). Until this observation was confirmed, and after the naming of the advaline adrenaline receptor has been resolved, it seems to be critical to point out that it is selective for the selected azova α-adrenergic receptor, as a choice Sexual ligands, unless selectivity to avar iA or avar 1 £ state can be demonstrated. The exact role of each of the Avarin-adrenergic receptor subclasses in various physiological responses is only to understand the beginning of the project, but it is clear that each subclass does mediate the difference between activators and anti-insertion agents reaction. For example, it has been shown that the contraction of the human prostate by noradrenaline is determined by the selected colony-9 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back first (Fill in this page again)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517049 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Invention Description (7) of Ava 1A_Adrenaline Receptor-Mediated (Ava 1L in Pharmacology -Adrenergic receptors; Forry et al., Molecular Pharmacology (1994) M: 70-708; Ford et al., Dad Pharmacology (1996) 49: 209-215) ° Has been It is clear that the role of the sympathetic adrenaline-induced nervous system in the bladder storage function (Wein; Latifpour et al., 1990) 2: 661 -667). Similarly, in this technique, it is understood that in the isolated urethra and bladder tissue (mentioned previously, Latifpour et al .; Tsujimoto et al., J. Pharmacol Exp. Ther, Π986 ) 211: 3 84-3 89). Researchers in each group have attempted to identify avar i-adrenergic receptor subclasses in humans, rabbits and rats through radioligand binding and functional studies (Yosjiida et al., J. Pharmacol Exp. Ther · (1991) 2 ^ 2: 1100-1108; aforementioned, Testa et al .; Chess-Williams et al., J. Auton. Pharmacol. (1994) il; 375- 38 1). So far, these efforts have not been able to respond to specific Aval! -The adrenergic receptor subclass is responsible for the adrenergic receptor activator function in the urethra and provides decisive evidence. It is known that certain Ava 1A-adrenoceptor (formally Ava 1C) agonists are useful in the treatment of urinary incontinence (Craig et al., WO 96/38143). Nasal congestion, about half of the resistance to airflow into the lungs, is provided by the nose and nasal cavity (Proctor, Am. Rev. Resp. Pis. (1977) 115: 97-129). The lining of the nasal cavity is menstrual Angiovascular connective mucosal layer. The bottom layer of the nasal mucosa is composed of anterior capillary resistance tubules, flowing into the posterior capillary venules and containing a ring. -10- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) ---------- * · * (Read the precautions on the back before you fill in this page) Order # 丨 Employee Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China Yinju 517049 A7 B7 V. Description of the invention (8) " ^ ~~~~ Shape and longitudinal smooth muscle bundle Sinuses, and arterial veins that connect blood around the capillary capillary network (Proctor et al., 1976) L493-509; Seaddilig, Clin Pyp ( 1995) 21; 391_394). This anatomical arrangement results in nasal mucosa, especially those lined in the middle and lower turbinates' and nasal septum, erectile tissue (Prpetor et al., 1976). Congestion of venous erectile tissue changes respiratory resistance and is important for the function of the nose # as an air conditioner. Vascular resistance and capacitive reactance in the nasal mucosa are fully innervated by autonomic nerve fibers. Adrenergic receptors have been known for decades to mediate the contraction of the nasal mucosa (Proctor et al., 1976). Indeed, this has formed the basis for treating nasal congestion with sympathomimetic agents. With the identification of different subtypes of avar-adrenaline receptors (Langer, Biocfaem. Pharmacol. (1974) 21: 1793-1800), it has been shown that aval and Avar r adrenaline receptor (lehmura et al., ArciL. Ortoriiolaryngpi (1988) 245: 127-13 1; Andersson et al., Ann._Qtol. Rhinol. Larvngol. (1984 ) il: 179-lS2). The presence of a pre-joint-inhibiting avanadrenaline receptor has been shown (Ichmura et al., Arch Otolaryngol (1984) 1Qj647_651). Both Ava and Adva 2_adrenergic receptors are thought to mediate vascular continuation of nasal mucosal vascular vessels (mentioned previously, Andersson et al .; previously mentioned, Scadding). It is believed that the reduction of vasoconstriction of volume vessels is caused by nasal congestion directly caused by the increase in sinus tension, while the contraction of resistance vessels indirectly reduces nasal congestion by increasing arterial resistance and thus reducing sinus filling (Lung et al People, Phvsiol · (1984) • 11-This paper size applies the Chinese National Standard (CNS) A4 specification (210 × Ϊ97 mm) ------;-sauce dressing--t (Please read the notes on the back first (Fill in this page again)

1.1T printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 517049 A7 B7 V. Description of the invention (9) 249.:535-551) 〇 The intranasal sympathomimetic agent used for the treatment of nasal congestion is divided into two basic chemical types , Named as specific β-phenylethylamines and imidazolines (Empey et al., Pharmacy (1981) 21: 438-443). Non-selective atorvaline adrenergic receptor antagonists, phenylephedrine test (Min [neman et al., Molecular Pharmacology (1994) j ^: 929-936), and mixed avatars " Avar adrenaline receptor antagonists (oxymetazoline) (previously, Minneman et al.) Are the representative substances currently used in these chemical types, respectively. The most related to intranasal sympathomimetics is drug-induced rhinitis, which is a type of M rebound associated with frequent and long-term (more than 7 to 10 days) drug use. The problem also leads to the danger of systemic side effects (except for the high incidence of the above-mentioned symptoms of Zhe Pei et al., The exact cause of which is not yet clear. Possible explanations for "M rebound" include the following. It may be caused by Avar The long-term or preferential tightening of the resistance blood vessels mediated by the hormone receptor may prevent the entry of oxygen or nutrients into the nasal mucosa, leading to the release of vasoactive mediators to counteract the congestion of the blood-sugar acid (B6rridge et al. Br J. Pharmacol (1986) 8 &:345-354; the foregoing, scutine. Long-term exposure to high concentrations of high-potency epinephrine-stimulating agents may also cause a decrease in adrenergic-stimulating receptors. Modulation or desensitization. That is, a decrease in the number of sensitive adrenergic receptors reduces the reactivity of both exogenous and endogenous sympathomimetic agents (previously, Shika Ting). Chemical irritation caused by an active ingredient or one of the ingredients may also cause drug-induced rhinitis (formerly, Scartin). -12- This paper size applies Chinese National Standard (CNS) A4 (2l0X297) (Mm) (Read the precautions on the back before filling in this page)

1T 517049 Printed by the Consumers' Cooperative of the Central Standards Bureau A7 B7 V. Description of the invention (10) Sympathomimetics used today lack selectivity for specific adrenergic receptor subclasses, and increasing the ability to develop will not cause Possibilities of effective intranasal sympathomimetics with medicinal rhinitis. For example, several imidazoline activators (such as oxymetazoline) have activator activity on both Ava and Ava? Adrenaline receptors (previously, Minneman et al.). So for Aval! _ Epinephrine receptors are selective activators that may not cause vasoconstriction of the nasal mucosal resistance vessels involved in the cause of drug-induced rhinitis (previously, Sca lights). Similarly, phenylephedrine will not be distinguished, and it has been sub-classified into each of the Avalon 1A-, Adva 1B- and Adva 1D-adrenoceptor subtypes within the last ten years. (Ford and others, the trend of learning (1994) !! _: 167-170). Therefore, it is possible that a single avar 1-adrenergic receptor subclass may selectively mediate vasoconstriction of the nasal mucosal sinuses, and thus do not produce a vasoactive adrenergic receptor subclass that can be mediated by other avarp adrenergic receptor subclasses. Harmful side effects. Other previous disclosures Esser et al., German patent 195 14 579 A1 (published on October 24, 1996) discloses benzimidin-imidazine compounds specifically for the treatment of urinary incontinence > it is a Aval 1L-actuator. Craig et al., WO 96/38143 (published on December 5, 1996) discloses the use of avalva-selective adrenergic receptor activators for the treatment of urinary incontinence. Purcell, U.S. Patent No. 4,492,709 (published on January 8th, 1985) discloses 2_ [4 (3) _amino-3 (4) -hydroxyl, which can be used to treat gastric acid secretion and hyperacidity. Phenylimino] • imidazole. Similar disclosures appeared in relevant Europe -13- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (read the precautions on the back before filling this page)

T 517049 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (11) Application 0 086 126 B1 (public address on July 24, 1985). Coquelet et al., U.S. Patent 4,665,085 (published in a column of May 12, 2007) discloses a method for preparing and treating specific amidines. A similar disclosure was found in the European patent application 0 132 19〇 B1 (published on January 13, 1988). The insecticidal aniline methylimidazolines were disclosed in Copp et al., U.S. Patent 4,414,223 (published November 8, 1983). Imidazolines with insecticidal activity are disclosed in Copp et al., Publication 27 56 638 (published on June 22, 1978), and related French patent license 862,022 (publicly granted in June 19, 1978). Sulfonamides of phenoxyacetic acid and imidazolin derivatives derived from phenoxyacetic acid and toluidine acetic acid derivatives, and their antihypertensive activity are provided by Gh. Botiz Et al. Are described in Academic Abstract 6834 (1964). Broersma et al., U.S. Patent No. 4,343,80 & (published August 10, 1982) discloses the use of specific phenoxy-, phenylthio-, or aniline-imidazoline compounds to inhibit sickle red blood cells. Into a sickle phenomenon. Reiter et al., U · κ · patent application GB 2 160 198 A (published on February 1S, I985) discusses certain specific imidazolines. Jones et al., WO 96/176 12 A1 (published June 13, 1996) discloses the use of new classes or known phenylguanidine or amine test derivatives to treat brain or heart hemorrhage or convulsions and sickle Cell anemia. Black et al., U.S. Patent No. 4,238,497 (published December 9, 1980) discloses imidazoline derivatives, their salts, and their use as pesticides. 14- This paper applies Chinese national standards (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

Printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517049 A7 _________ V. Purpose of Invention Statement (12). Aval IA. The use of selective adrenergic receptor activators for the treatment of urinary incontinence is discussed in Craig et al., U.S. Patent 5610, 74 (published on March 11, 1997 ). Prasit et al., European Patent Application 0535 923 A1 (published on April 7, 1993) discloses (nitroarylmethoxy) tablets as leukotriene biosynthesis inhibitors . (Aromatic alkoxy) indoles as inhibitors of leukotriene synthesis are disclosed in Frenette, WO 93/16069 (published on August 19, 1993). Aslanian et al., U.S. Patent 5,578,616 (published on November 26, 1996) discloses certain benzalkolides that have pharmacological properties, particularly CNS activity and combat inflammatory diseases. Morino et al., U.S. Patent 5,36,0,822 (published November 1, 994) disclose specific sulfanilide derivatives that are useful as urinary incontinence drugs. Wismayr et al., U.S. Patent No. 3,340,298 (published on September 5, 1967) discloses phenylammonium amine derivatives that are specifically useful in the treatment of hypertension. Winn et al., U.S. Patent 4,665,095 (published on May 12, 1987) disclose specific imidazolines that can be used to treat nasal congestion. Robertson et al., U.S. Patent 4,956,388 (published on September 11, 1990) discloses specific 3-aryloxy-3-substituted propylamines that are useful for inhibiting% uptake of tryptamine and norepinephrine. -15- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

517049 A7 ____________B7_ V. Description of the Invention (13) Gluchowski et al., U.S. Patents 5,40,3,847 (published on April 4, 1995) and 5,578,611 (published on November 26, 1996) disclose specific (X1C-specific compounds that can be used to treat benign prostatic proliferation. Cupps et al., U.S. Patent No. 5,541,2 10 (published June 30, 1996) discloses specific uses for the treatment of respiratory ridges, eyes, and Avar 2-adrenoceptor activator for gastrointestinal disorders. Bard et al., US Patent 5,556,753 (published September 17, 1996) discloses specific human adrenergic receptors Extremely useful. See also WO 94/08040 (published on April 14, J994). Meyer et al., US Patents 5,597,823 (published on January 28, 1997) and 5,578,611 (published on 1996 (November 26) Reveals a specific tricyclic substituted hexahydrobenzo (E) isoindenone avalin-1 adrenaline-agonizing antagonist that can be used to treat benign prostate proliferation. Jeon et al., WO 97 / 31636 (published on September 4, 1997) Revealing Specific Pair Selection The selective adol and benzopeptone derivatives of human α2 receptor were obtained. Wong et al., WO 97/42956 (published on November 20, 1997) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Fan (please read the notes on the back before filling out this page) Reveal the dihydropyrimidine compounds that are specific to human αι receptor antagonists. Jeon et al., WO 96/04270 (published in February 15, 1996) Reveals a benzimidazole derivative that is specifically selective for selected colonized human avalin 2 receptors and can be used as an analgesic, sedative or anesthetic agent. The present invention relates to a compound represented by formula 1. Novel compounds: ___ -16- This paper size applies to Chinese national standards (CNsT ^ ST ^ 297 mm)-517049 A7 —_________________ One B7 V. Description of the invention (14) R4

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs where 1 is < 〇1311,) said (defeated 111 and (1 are 0 or 1, respectively, when the bismuth is S q is 1, then m is 0, and When _ 〇, the claw is i; 2 is c = 〇 or S〇2; η is 1, the condition is that when mc = = 〇 μ i · 乂 is _ leg_, CH2 or 〇CH2_, γ is 2 -Imidazoline, 2-P-oxazole, 2-tetrazole-Plin or 4-miazole, R is H, lower alkyl or phenyl, provided that & 1 is] 9 [, then m Is 1, and R, r, and R60 are each independently H, a low-carbon alkyl group or a phenyl group; RR, κ, and trans 7 are each independently hydrogen, a low-carbon alkyl group, -CF3, a low-carbon alkoxy group, Halogen, phenyl, low-carbon alkenyl, hydroxyl, low-carbon alkanesulfonamido, or low-carbon cycloalkyl, where R2 and R7 can form a co-located, unsubstituted or substituted 5_ Or a 6-membered ring with an alkylene or alkenyl group of 2 to 3 atoms, where the optional substituent on the ring is halo, low-carbon alkyl, or -CN ', provided that R7 is hydroxyl Or a low-carbon alkylsulfonamido group, then X is not _NH • when Y is 2-imidazoline. These compounds include the above compounds Pharmaceutically acceptable salts. In the above formula, A (for example) may be (Rhc ^ NR2-), (R3R60NSO2NR2 ·), or (R3R60NCONR2-). A preferred compound of the present invention is a compound represented by Formula 2: -17- This paper rule money_Home Standard (CNS) ϋ ^ ΤΊϊ〇Χ 29 ^ 7 -------- Tube II "; (Please read the precautions on the back before filling this page), 1T 517049 A7 B7 V. Description of the invention / 15 R9 R1〇R8S〇,, χεγβ

Where: χΐ-ΝΗ-, -CH2- or -〇CH2-; Ya is 2-imidazoline, oxazoline, 2-, oxazoline or 4-imidazole, especially 2-imidazoline or imimidazole; ^ Are low-carbon alkyl, phenyl, or -NR14R15; R9, Ri4, and Ri5 are each independently fluorene or low-carbon alkyl; R1G, Rii, and r! 3 are each independently hydrogen, low-carbon alkyl,- CF3, low-carbon alkoxy, halogen, phenyl, low-carbon fluorenyl, unsubstituted, low-carbon sulfonamido, or low-carbon cycloalkyl, which can be co-formed with R13 if necessary, Unsubstituted or substituted 5 • or “alkylene or alkenyl group with 2 to 3 atoms in the member ring, provided that when it is a hydroxyl group or a low-carbon alkylsulfonamido group, the meaning is ¥ is In the case of octamidazoline, it is not -NH-. These compounds include the pharmaceutically acceptable classes of the aforementioned compounds. The preferred compound of the present invention is a compound represented by Formula 3: 6-13 Salts --------- Two J (Please read the notes on the back before filling in this page j,-Central Standard of the Ministry of Economy Printed by the Bureau's Consumer Cooperatives R17 R18 R16S〇pN ^ 丄 nh-Yb

In 20, ^ is 2-imidazoline; R17 is fluorene or low-carbon alkyl; R18, R, and R are each hydrogen, low-carbon alkyl, _cF3, low-carbon alkoxy, or fluorene Vegetarian. These compounds include the pharmaceutically acceptable salts of the aforementioned compounds. 19 Bang · -18- This paper size is in accordance with Chinese National Standard (CNS) A4 (2 Shu 297 public directors) 517049 A7 B7 5. Description of the invention (16 The preferred compound of the present invention is a compound represented by Formula 4: R23 R24 R22so2nv ^ > v_ch2-yc R27〆 * R25 R: 26 where: Y. is 2-imidazoline or 4-imidazole; R22 is a lower-carbon alkyl group; R23 is H or a lower-carbon alkyl group; R24, R25 , R25 and R27 are each independently hydrogen, low-carbon alkyl, low-carbon alkoxy, halogen, phenyl, low-carbon alkenyl, hydroxyl, or low-carbon fluorenamine. These compounds include The pharmaceutically acceptable salts of the above compounds. The preferred compounds of the present invention are compounds represented by Formula 5: R29 r30 R28SOpN ^ ″, OCH2-Yd (2N ^ J \ 〇CH2) 33 r31 R32 5

Among them: Y ^ 2 · midazoline or 4-imidazole, · R28 is a low-carbon alkyl group, · R29 is a low-carbon alkyl group printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy; R3G, R31, 1 ^ 32 and 1 ^ 3 are each independently hydrogen, low-carbon alkyl, halogen, hydroxyl, or low-carbon cycloalkyl. When 0 is 2-imidazoline and R or R is not Η, the present invention includes subgroups in which r30 or r33 is not Η. These compounds include the pharmaceutically acceptable salts of the aforementioned compounds. The preferred compound of the present invention is a compound represented by Formula 6: 19- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 male sauce) -------- Shenyi ------ 1Τ ------ (Please read the notes on the back before filling out this page) 517049 A7 B7 V. Description of the invention (17 Η 534 rS〇2 \ 入, _Yb R35 Among them: Yb is 2 • imidazoline; Ru is Low carbon number alkyl; r34, r35, and R36 are each independently fluorene, a, Br, p or low carbon number. These compounds include the pharmaceutically acceptable salts of the above compounds. The present invention < Preferred compounds Is a compound represented by Formula 7:

In h, Ye is 2-imidazoline or 4-imidazole; R22 is a low-carbon alkyl group; R: R and R36 are each independently H, α, Br, F, or a low-carbon alkyl group. These compounds include the pharmaceutically acceptable salts of the aforementioned compounds. The preferred compound of the present invention is a compound represented by Formula 8: H R34 R28SO 丄, 〇CH2-Yd • 34 Printed by the Consumers Cooperative of the Central Standards Bureau of Didi Ministry

Among them: Yd is 2. imidazoline or 4-imidazole; r28 is a low-carbon alkyl group; f R and R36 are each independently H, C, Br, f, or a low-carbon alkyl group. These compounds include the pharmaceutically acceptable salts of the aforementioned compounds. The preferred compound of the present invention is the compound represented by Formula 76: * 34 -------------- Order ------ AWI (Please read the precautions on the back before filling in this (Page) -20 This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 517049 A7 B7 V. Description of the invention / 18 R55〇

χ ^ —γ9 R58 76 where X% -NH-, -CH〇ch2-; Yl 2-imidazoline, 2.oxazoline, 2-oxazoline or 4-imidazole; R55 is a lower carbon number alkyl Or r56 forms part of a substituted or optionally substituted 5_ or ... member ring, where the optional substituents on the rubber are halogen, lower alkyl or _CN, and r56 is (CH2) k, Where k is 1 or 2 and is CH = CH, CH = CHCH2, or < ^ ί2 (: ίΙ = (: Ιί; R57, ruler and! ^ Are each independently hydrogen, a low-carbon alkyl group, -CF3, Low-carbon alkoxy, halogen, phenyl, low-carbon alkenyl, hydroxyl, low-carbon sulfofluorenylamino, or low-carbon cycloalkyl. These compounds include the pharmaceutically acceptable salts of the above compounds The preferred compound of the present invention is a compound represented by Formula 75: r48so

X1—Yf, 51 Among them: X1 ^ -NH-, -CH2: i -〇CH2-; Y1 ^ 2_oxazoline or 2- 喽 --------— § (Please read the Note: Please fill in this page again.) Order # 1 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs; R48 is a low-carbon alkyl group; r49 is a fluorene or a low-carbon alkyl group; R5G, R51 »53 R and R53 each Independently is hydrogen, low-carbon alkyl, -CF3, low-carbon alkoxy, halogen, phenyl, low-carbon fluorenyl, hydroxy, low-carbon sulfonamido, or low-carbon cycloalkyl In which, R49 and R53 can form an alkylene group or a fluorenyl group having 2 to 3 atoms in a 5- or 6-membered ring, if necessary. These compounds -21-This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) The preferred compound of the present invention is the compound represented by Formula 74: R42 R44

517049 A7 __ · _ B7 V. Description of the Invention (19) The substance includes the pharmaceutically acceptable salts of the above compounds. Among them: XUH-, -CH2- or -OCH2-; Ye is imimidazoline, mozolazole, 2 ^ cetoline or 4-imidazole; R41, 1 ^ 42 and R43 are each independently H, phenyl or low Carbon number alkyl; R44, R45, 1146 and & 47 are each independently hydrogen, low carbon number alkyl, -CF3, low carbon number alkoxy, halogen, phenyl, low carbon number fluorenyl, meridian, low Carbon number alkylsulfonamido group, or low carbon number cycloalkyl group, in which R42 and R47 can be co-formed to form an alkylene group or an alkylene group having 2 to 3 atoms in a 5- or 6-membered ring, if necessary. These compounds include the pharmaceutically acceptable salts of the aforementioned compounds. The present invention also includes compositions suitable for administration to mammals (especially humans) having a disease state that can be alleviated by treatment with avar ... κ adrenergic receptor activators, the composition comprising a therapeutic An effective amount of a compound having each of the above formulas, or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for treating mammals (especially humans) having a disease state that can be alleviated by treatment with a ha / il adrenergic receptor activator, comprising administering a therapeutically effective amount of each of the above Compounds of molecular formula, or pharmaceutically acceptable salts thereof. The present invention also includes a method for treating mammals (especially humans) with urinary incontinence, which includes a combination of effective IT with the above-mentioned molecular formulas for the administration of drugs ------ ^ ___ w ~ (Please read the note on the back (Please fill in this page for matters)

517049 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 V. Description of Invention (20) Objects' or their pharmaceutically acceptable salts. The present invention also includes a method for treating mammals (especially humans) having nasal congestion, which comprises administering a therapeutically effective amount of a chemical compound 'having the above-mentioned molecular formula' or a pharmaceutically acceptable salt thereof. > This month also includes treatments for patients with abnormal erections, anxiety, anxiety, fatigue, aging, Alzheimer's disease, lack of attention and discrimination, or eating disorders such as obesity, bulimia, and anorexia A method for mammals (especially humans), which comprises administering a therapeutically effective amount of a compound having each of the above formulae 'or a pharmaceutically acceptable salt thereof. The present invention also relates to novel intermediates, and to pharmaceutical compositions containing a compound having each of the above formulas < compounds and one or more pharmaceutically acceptable, non-toxic carriers. The present invention also relates to compounds having the above-mentioned molecular formulae as pharmaceutically active substances. The present invention also relates to the compound% with each of the above-mentioned molecular formulas, which is used to prepare pharmaceuticals for preventing and / or treating disease states that can be slowed down by treatment with avar 1A / 1L adrenaline receptor activator. The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound according to each of the above molecular formulas in combination with a therapeutically inert carrier. The present invention also includes a pharmaceutical composition comprising a therapeutically effective amount of a compound according to each of the above molecular formulas, and a therapeutically inert carrier and / or additionally useful for prevention and / or treatment. Receptor agonists are treated with a combination of compounds that result in a slowed disease state. The present invention also includes compounds having the above-mentioned molecular formulas for use in the manufacture of medicines. ____ -23- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (21〇 × 297 mm) -------- ΙΜΨ-- ---- 1Τ ------ 0— (Please read the notes on the back before filling out this page) 517049 A7 --------_______ B7 V. Application of the invention (21) This month also includes compounds with the above formulas for the manufacture and prevention of urinary incontinence, nasal congestion, abnormal erections, depression, anxiety, dementia, aging, Alzheimer's disease, attention And the use of pharmaceuticals for lack of discrimination and / or eating disorders such as obesity, bulimia and anorexia. The present invention also includes compounds having the above-mentioned molecular formulae obtainable by the methods described herein. The present invention also relates to a method for treating and / or preventing a disease state that can be alleviated by treatment with adrenaline agonists with avar, which comprises administering a therapeutically effective amount of a compound having each of the above formulas. The present invention includes for the treatment and / or prevention of urinary incontinence, nasal congestion, abnormal erections, depression, anxiety, dementia, aging, Alzheimer's disease, lack of attention and identification, and / or eating disorders such as A method for obesity, bulimia, and anorexia, which comprises administering a therapeutically effective amount of a compound having each of the above molecular formulas. The Printing Association of Employees' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs II, I (Please read the notes on the back before filling out this page) The present invention provides methylphenyl, methoxyphenyl, and aminophenylalkylsulfonium Various types of amines and hides 2 · Junjun Lin, 2-4 Junlin, 2-Yuanjunlin and 4 • Mijun derivatives, and their use in the treatment of various disease states including urinary incontinence, nasal congestion, abnormal erections, Depression, anxiety, dementia, aging, Alzheimer's disease, lack of attention and discrimination, and use of eating disorders such as obesity, bulimia, and anorexia. For example, the compound of the present invention is an adrenaline receptor agonist that is selective and orally active for medical use to treat mild to moderate 中 positive depressive urinary incontinence. Due to the increase of these compounds-24- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 Μ B7 V. Description of the invention (22) A low-purity diarrhea printed by a staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Smooth muscle tone is selective with little or no effect on the vasculature (ie, vascular continuity), heart, or central nervous system (CNS). That is, before proceeding to describe the preferred embodiment of the present invention, the final terminology will be defined first. When used herein: "Carbonyl" means a branched or unbranched saturated monovalent hydrocarbon radical containing 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, p- " butyl, N-hexyl, n-octyl, etc. "Low carbon number alkyl" means a branched or unbranched saturated monovalent hydrocarbon radical containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, di-di "butyl, Butyl, n-pentyl, etc. "Low-carbon alkoxy" means the group _0_ (low-carbon alkyl), wherein low-carbon alkyl is as defined herein. Cycloalkyl means a saturated monovalent monocyclic hydrocarbon radical containing 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like. 'Low carbon number alkylene' means a branched or unbranched saturated monovalent fe radical containing 1 to 6 carbon atoms, such as methylene, ethylidene, propylidene, 2-methylidene Radicals, 1,2-dimethylpropanyl, pentyl, etc. "Low carbon number alkyl" means containing branched or unbranched unsaturated fe radicals containing 2 to 6 carbon atoms, For example, ethenyl, acryl, n-butyral, isopropenyl, isobutenyl, n-pentenyl, isopentenyl, and the like. -25 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) (Read the precautions on the back before filling this page) ► 、 \ 呑 4 Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperative 517049 A7 _ — _ B7 V. Description of the invention p) “Low carbon number alkenyl group” means a branched or unbranched unsaturated divalent hydrocarbon radical containing 2 to 6 carbon atoms, such as acetylene, propylene Group, 2-methylpropenyl, 1,2-dimethylpropenyl, pentenyl, and the like. "Inert organic solvent or inert solvent" means a solvent that is inert under the reaction conditions in which it is combined, and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran (" THF "), dimethylformamide (, , DMF, f), chloroform (" CHC13 "), dichloromethane (" CH2C12 "), diethyl ether, ethyl acetate, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tertiary butanol, di Pinane, pyridoxine, etc. Unless otherwise specified herein, the solvent used in the reaction of the present invention is an inert solvent. "Halogen" means fluorine, chlorine, bromine, or iodine. "Halo" means fluoro, chloro , Bromo, or iodo. Halide means fluoride, gaseous, bromide, or iodide. Phenyl means all possible allotype phenyl radicals which are mono- or di-substituted with substituents selected from the group consisting of lower alkyl groups, lower alkyl groups, and halogens, as necessary. "Phenyl lower alkyl" means that a phenyl group, as defined above, is attached to a lower alkyl group, as defined above. 2-Mi Junlin means the part indicated by the following structure:

It must be understood that the double bond located in the 2-imidazoline is sufficient depending on the nature of X in each of the above molecular formulas, and presents other resonance forms. When 乂 is ..., the appropriate form of resonance is the following: -26- The paper size is suitable for wealth _ house standard 29 Han -------- Cao ——, * (Please read the notes on the back before filling (This page)

1T 517049 V. Description of the invention (24

__-— Μ • Ν

The term 2-imidazoline includes all such resonances 2 · oxazoline "means the moiety indicated by the following structure ...

The term 2-oxazoline includes all such resonance forms. "2-, oxazoline" means a moiety represented by the following structure:

S- I 1 n-n I I I I I * (read the first reading on the back and read the weeping note on this page) The term 2_oxazoline includes all such resonance forms. "W4-imidazole" means the part indicated by the following structure ... 3n ^ \. It should be understood that various numbers have been used in the above list. The position 4 cited in the above formula is based on the above formula with nitrogen It is an indication of the number i. However, if the following semi-arrangement is used, then the attachment position of the compound in the compound of the present invention will be 5-position: printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Foreign Affairs 1 Η Another arrangement The method is used to indicate the attachment position of 4 (5) -Misal. "Pharmaceutically acceptable salts" means those who are still in a free state. 27- This paper applies Chinese national standards (CNS ) A4 specification (210 '乂 297 mm) 517049 A7 B7 V. Description of the invention (25) Physical properties and characteristics, and not biologically or undesirably salts, it is treated with inorganic acids such as hydrochloride Acids, succinic acid, sulfuric acid, nitric acid: phosphoric acid, etc., and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid Diacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Formed by acids, methanesulfonic acid, acetic acid, para-acetic acid, salicylic acid, etc. I wish or need to mean that the event or environment described later may or may not occur, and the statement Includes cases where the event or environment will occur, and cases where the event or environment will not occur. For example, w is substituted phenyl as needed, meaning that the phenyl may or may not be substituted, And the narrative includes both unsubstituted phenyl and substituted phenyl; "the subsequent conversion of a free-state base to an acid addition salt, if necessary, means that the conversion may or may not be completed so that The described method is included in the present invention, and the present invention includes the method in which the free state test is converted into an acid addition salt, and the method in which this step is not performed. Isomers are different compounds with the same molecular formula. 'Treatment' means any treatment performed in mammals (especially humans) and includes: Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) (i) Prevent the disease Occurs in individuals who may be pre-diseased but have not been diagnosed with the disease. (ii) inhibit the disease, that is, stop its development; and / or (iii) slow the disease, that is, cause the disease to decrease. ”Can be slowed down by treatment with Avar-1 adrenergic receptor activator-28- This paper size applies the Chinese National Standard (CNS) A4 size (210X297 mm) 517049 Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Print A7 B7 V. Description of the invention p) Disease states "for the purposes of this article, all disease states generally known in the art that can be usefully treated with avar 1 adrenergic receptor activators, and Wei et al. Have found a disease state that can be effectively treated by the specific avar 1 adrenaline incinerator activator (a compound having each of the above formulas) of the present invention. These disease states include, for example, urinary incontinence, nasal congestion, heterodyne erection, depression, anxiety, dementia, aging, Alzheimer's disease, lack of power and discrimination, and eating disorders such as obesity, bulimia, and Anorexia. A "therapeutically effective amount" means the total amount sufficient to effectively treat (as defined above) when administered to a mammal in need of such treatment. A therapeutically effective amount will depend on the individual being treated and the state of the disease and the severity of the disease And the method of administration vary, and can be determined by those skilled in the art in accordance with the convention. Preferred specific examples in the compound Yang group of the present invention, the preferred group includes the following formula 1 compounds: (R3R60NSO2NR2-) or ( R3R60NCONR2-); X is -NH-, -CH2-, or -OCH2-; Y is 2-imidazoline, 2-xantolin, 2-pyrazazoline, or 4-imidazole; R1 is fluorene, low-carbon alkyl Or phenyl; R2, R3, each independently is fluorene, low-carbon alkyl or phenyl; R4, R5, R6 and R7 are each independently hydrogen, low-carbon alkyl, -CF3, low-carbon-29- this paper The dimensions are applicable to China National Standard (CNS) A4 specifications (210X297 mm) -------------- IT ------ (Please read the precautions on the back before filling this page)

Among them 517049 A7 B7 V. Description of the invention (27-numbered alkoxy, halogen, phenyl, low-carbon number alkenyl, hydroxyl, low-carbon number alkylamino, or low-carbon ring group, where R2 and R7 are regarded as Need to be able to jointly form an unsubstituted or substituted 5- or 6-membered ring with 2 to 3 atoms of an alkylene or alkenyl group, where the substituent is located in the ring of soil as needed The number of groups or -CN, provided that when R7 is a group or a low number of sulfonamides, then X is not -NH- when the group is 2-imidazoline. These compounds include the above compounds Pharmaceutically acceptable salts. The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is printed in the above formula 1. Other preferred embodiments include methyl, ethyl, propyl, or phenyl; 1 Acceptable salts. Other preferred embodiments include hydrogen except for one of R4, R6, and R7, and the remaining one is selected from methyl, ethyl, -CF3, and methyl. Oxygen, gas, bromine, fluorine, isopropyl, cyclopropyl, vinyl, unradical, and methylenesulfonylamine; or pharmaceutically acceptable Salts. Still other preferred embodiments include hydrogen except for R4, R5, R6, and R7, and the remaining two are independently selected from fluorenyl, 6-based, Isopropyl, -CF3, chlorine, bromine, and fluorine; or pharmaceutically acceptable salts thereof. Yet other preferred embodiments include, wherein ... and R7 together form an unsubstituted or substituted 5-membered ring Extender vinyl, in which the substituents on the ring are optionally substituted, alkyl with lower carbon number * _cn, preferably chlorine, bromine, or -CN; or pharmaceutically acceptable salts thereof. R11, R12 and The rest of R13 is hydrogen, and the remaining -------- • clothing-•-(Please read the precautions on the back before filling out this page), 11 in Equation 2 above, Preferred specific examples include wherein R8 is an ethyl group, an ethyl group, a propyl group, a phenyl group, an amine group, a methylamino group, or a dimethylamino group; or a pharmaceutically acceptable salt thereof. Other preferred specific embodiments include among them apart from

R -30- Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of Didi Ministry 517049 A7 ___________ B7 V. Description of the Invention (28) The remaining one is selected from methyl, ethyl, -CF3, methoxy, chlorine, bromine, fluorine , Isopropyl, cyclopropyl, vinyl, hydroxyl, and mesylamine; or pharmaceutically acceptable salts thereof. Still other preferred embodiments include hydrogen except for R1G, R11, R12, and R13, and the remaining two are each independently selected from methyl, ethyl, isopropyl, , Chlorine, bromine, and fluorine; or their pharmaceutically acceptable salts. Still other preferred specific embodiments include wherein R9 and R9 together form a vinyl group in an unsubstituted or substituted 5-membered ring; or a pharmaceutically acceptable salt thereof. In the above formula 3, a preferred embodiment includes the formula 1 is methyl; or a pharmaceutically acceptable salt thereof. Other preferred embodiments include hydrogen except for one of R18, R19, and one of the remaining is selected from methyl, ethyl, isopropyl, and π. , Methoxy, fluorine, chlorine, and bromine; or a pharmaceutically acceptable salt thereof. Still other preferred embodiments include hydrogen except for Ris, R19, R20 and the other two, and the remaining two are each independently selected from methyl, ethyl, isopropyl, -CFS, fluorine, gas, and bromine; or their pharmaceutically acceptable salts. Still other preferred embodiments include, wherein Rle is methyl and R17 is hydrazone; or a pharmaceutically acceptable salt thereof. In the above formula 4, preferred embodiments include wherein r22 is methyl, ethyl, or isopropyl; or a pharmaceutically acceptable salt thereof. Other preferred specific embodiments include them! ^ Is chlorine or methyl; or a pharmaceutically acceptable salt thereof and other preferred embodiments include that except for one of R24, R25, r? 6, and R27, all are chlorine, and the remaining one This is selected from methyl, ethyl, isopropyl, vinyl, C] p3, methoxy, hydroxy,, and clothing — 9 | (Please read the precautions on the back before filling this page}

、 1T .__ -31 517049 A7 B7 V. Description of the invention (29) Printing of phenyl, fluorine, gas, bromine, and methylamino groups by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs; or its pharmaceutically acceptable form . Still other preferred embodiments include hydrogen except for R24, R25, R20, and R27, and the remaining two are independently selected from methyl, ethyl, gas, and bromine. ; Or its pharmaceutically acceptable salt. Still other preferred and specific embodiments include, wherein # is 2-imidazoline or 4-imidazole, R22 is methyl, and H23 is ^ 1; or a pharmaceutically acceptable salt surface thereof. In the above formula 5, the preferred embodiments include the formula 28 in which fluorenyl, ethyl, propyl, or phenyl; or a pharmaceutically acceptable salt thereof. Other preferred embodiments include hydrogen except for one of r30, Rh, rulers 32, and 33, and the remaining one is selected from cyclopropyl, gas, fluorine, hydroxyl, and methyl. , And ethyl; or a pharmaceutically acceptable salt thereof. Yet other preferred examples include those in which all except hydrogen grave 30, R32, and R are hydrogen, and the remaining two are independently selected from methyl, ethyl, chlorine, With bromine; or its pharmaceutically acceptable salts. Still other preferred embodiments include one of which is: 2 • imidazoline or 4 • imide. R28 is methyl, is methyl, and R33 is halogen; or a pharmaceutically acceptable salt thereof. Still other preferred embodiments include one of which is imidazoline, R28 is methyl, is methyl, and R33 is chlorine or bromine; or a pharmaceutically acceptable salt thereof. In the above formula 6, preferred embodiments include wherein R16 is methyl; or pharmaceutically acceptable salts thereof. Other preferred embodiments include wherein no more than one of R, R, and R36 is ^, ^, or F; or a pharmaceutically acceptable salt thereof. Still other preferred embodiments include R34, R35 33 2 · Doctor (read the precautions on the back before filling out this page), 1T # π. -32- 517049 A7, invention description (30 employees of the Central Standards Bureau of the Ministry of Economic Affairs Consumption cooperatives and R36 each have 3, ¾, and ¾ on each other as H, α, Br, F, methyl, or ethyl; or acceptable salts on their beams. JIE # In formula 7, the better Specific embodiments include wherein r22 is methyl, or has a medical salt, 34 35 can be connected to crossbow salts. Other preferred specific embodiments include where no more than one of Ding, R and R36 is 0, 仏, or F; or 36 medicaments thereof. Still other preferred embodiments include R34, R35: each of the bracelets is H, C, F, methyl, or ethyl; or pharmaceutically acceptable salts thereof In Formula 8 above, preferred embodiments include R28 is methyl; or a pharmaceutically acceptable salt thereof. Other preferred embodiments include R34n ^, and no more than one of R is Cl , Br, or F; or its pharmaceutically acceptable salt 6 and other preferred embodiments include R34, R35, and f6 each independently Is H, C, Br, F, methyl, or ethyl; or a pharmaceutically acceptable salt thereof 6 in the above formula t6, and preferred embodiments include R56 is CH € UR, R 8 and r 5 9 Is H, and yg is Mi Junlin; or a pharmaceutically acceptable salt thereof. F is in the above formula 75, and the preferred specific examples include the " is 41, Y, 2-oxazoline, R48 and r5. Is CH3, and R49, r51, r5, and r53 are fluorene; or a pharmaceutically acceptable salt thereof. In the above formula 74, preferred specific examples include wherein Xe is _OCH2-, Ye is 2-imidazoline, and 41 and ruler 43 are CH3, and r42 r44 r45R40 and R47 are rhenium; or pharmaceutically acceptable salts thereof. The following compounds of formula 1 are prepared: 33- The size of this paper applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm)

I I —i I I ― · I I I clothing — I •: / (Please read the precautions on the back before filling out this page) 517049 A7 —-------- B7 V. Description of the invention (31)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

It generally involves the introduction of the " A " part and, ·, X-Υ " part into the benzene ring. The following discussion of flowcharts A-E involves the separate introduction of the above sections. It should be understood that with regard to any given compound, the import of these two parts must be considered. Therefore, the following discussion of the flowcharts A-E is for the purpose of illustration, not limitation. Usually, the effect of introducing A into the above-mentioned compounds. It depends on the nature of a. Wherein A is RiSC ^ NR2- or R3R60NC〇NR2-, and the amino group is introduced into the structure through the action of appropriate commercially available components' or its synthesis into a known aminophenyl compound. If such an aminophenyl compound is not commercially available 'or its synthesis is not known, the corresponding nitrophenyl compound' can be used and the nitro group can be reduced to an amine group by an appropriate method. If the desired phenyl compound is also not available, the nitro group can be introduced into the appropriate phenyl compound by known techniques. The amine group is reacted with an appropriate fluorinated halide or an acid anhydride. The introduction of part A can be illustrated by the following flow chart A: Flow chart A

-34- The size of this paper applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -------- clothing — chip (please read the precautions on the back before filling this page)-, 1Τ 517049 kl _B7 ~ — * —. 一 _____ ~ —-------- _ V. Description of the invention (32) The amine group and the appropriate alkanesulfone group compound (Rhc ^ v, where V is Halides), such as gasification of alkylsulfonyl groups, to give the desired alkylsulfonamide. Various methods can be used for the introduction of the X- 各种 part. In a pathway in which 2-imidazolyl group is introduced into a precursor compound in which X is -CH2-or -〇CH2_, the cyano group is converted to fluorenimide functionality, and it is combined with the 1,2-diamine group. Ethane is condensed to form 2-imidinoline. This approach is illustrated in flow diagram B:

Flowchart B (Please read the notes on the back before filling this page) R4 R4

Alternatively, the cyano group can be reacted with ethylenediamine and trifluorenyl aluminum in refluxing toluene to directly form 2-imidazolinyl (Wentland et al., J Med. Chem. (1987) 30: 1482).

OR R5 NH 37 Printed by another consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, which introduces 4 · imidazolyl in which X is -CH2_ or -〇CH2- precursor compounds, which converts the cyano group into an aldehyde. It reacts with fluorenylmethyl isocyanide to obtain hydroxyhumidazole (Buchi et al., Heterocyclic-35) This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) 517049 A7 B7

V. Description of Invention (33) Lian J 1994) 12J 13 9). Imidazolyl is produced by treating the above compounds with ammonia. This approach is illustrated in Flowchart C: Flowchart C

(Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

In another approach of introducing a 2-imidazoline group in which X is -NH-precursor compound, the amine group is reacted with the 2-imidazoline group to directly produce the desired compound. As mentioned above, the amine group can be introduced into the benzene ring by reducing the nitro group. The latter compounds may be commercially available or their synthesis may be known. Alternatively, the nitro group can be introduced into the benzene ring as described above. This approach is illustrated in Flowchart D, where the V portion of the reagent is halogen or SCH3, and where (when V is SCH3) the reagent is a hydrogen iodide: Flowchart D

-36- This paper size applies to China National Standard (CNS) A4 (210X297mm), 1 '517049 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

21 A7 B7 V. Description of the invention (34 For those compounds where A is R3R60NS〇2NR2-, the following illustrative flow chart E can be used. The amine group in the precursor compound and the appropriate amine sulfonium compound (WOnsc ^ v1, where V1 is a halide).

Flowchart E

X-CN R5 R6 19 The following reaction schemes for the preparation of certain compounds according to the invention are illustrated in a more detailed manner, one or more of the general synthetic routes described above. Scheme F outlines a route to prepare a compound of formula 1 where A is R ^ SC ^ NH-, X is .CH2- or -0CH2-, and Y is 2-imidazoline.

Flowchart F

X 一 CN R5 -37- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297mm) (Please read the precautions on the back before filling this page}

517049 A7 B7 V. Description of the invention (35 R1S〇 ‘

X—CN pOCgH 5 NH 25

X ~ CN -► Η R4

R5 When the staff of the Central Bureau of Standards of the Ministry of Economic Affairs consumes R-Rx-CI, this approach involves compound 21 and cyanide ions (such as 21 to 0.5 per mole of compound) J 3, preferably 1 to 2 moles), is reacted in an inert organic solvent such as dimethylformamide, ethanol, monooxane and the like. The reaction can be further completed by including catalysts such as sodium iodide, potassium iodide, lithium iodide and the like. The reverse shoulder is about 60 to 90T :, preferably 70 to 80. (: The temperature is usually completed under an inert gas such as nitrogen, argon, etc., which takes about 1 to 24 hours, preferably 12 hours. By cooling the reaction mixture to the surrounding temperature, the reaction mixture is immediately It is mixed with ethers such as i to 20, preferably 5 to 10 times the amount, such as monoethyl ether, dimethoxyethane, diuridine, tetrahydrofuran, etc., to separate the resulting products. The resulting product (compound 22) is then washed with a saturated salt solution such as saturated steel chloride. When X is -OCH2 · and R70 is -0-, compound 21 can be halogenated with acetonitrile ', such as BrCHsCN. Or cyanomethyl sulfonate, in the presence of strong bases such as sodium hydride, NaN (TMS) 2, or KOtBu, etc., suitable for organic solvents -38- This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) — t- '(Please read the notes on the back before filling out this tribute) 517049 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (36) Such as monomethylformamide, two , And other alkane, tetrahydrofuran and other types of treatment, and the introduction of CN-based hydrazone. Usually per mole The product 21 uses 0 to 3, preferably 1 to 2 moles of acetonitrile. The reaction is completed by adding the hydride to a solvent cooled in an ice bath, and then warming to room temperature. Compound 21 is added to a solvent which is cooled in an ice bath. The reaction takes about 1 to 24 hours, preferably 3 to 12 hours to complete. The resulting product (chemical product 22) is then recovered. In another In an alternative specific example (X is -0Ch2- and R7G is -0Η), compound 21 can be prepared by _-acetacetonitrile, such as BrCH2CN, in the presence of Cs2C03, K2C03, etc., and methyl ethyl ketone, acetone, etc. In the process, the CN base ring is introduced. Generally, about 1 to 4 ′ is preferably 2 to 3 mol of Cs2C03, and about 0.3 to 3, preferably 1 to 2 mol of halogen per mole of compound 2i. Acetonitrile. The reaction takes about 1 to 24 hours, preferably 2 to 6 hours to complete. The resulting product (compound 22) is then recovered. Compound 22 is then treated to reduce the nitro (ie, hydrogenate) ) And amino group. This can be done in a number of ways, for example, in one route, compound 22 is inertly soluble For example, ethyl acetate, methanol, ethanol, etc., can be hydrogenated with a suitable exogenous catalyst such as palladium on carbon, platinum oxide, or rhodium on aluminum to obtain compound 23. For example, for each gram of compound 22 added In other words, 0.01 to 0.1 g, preferably about 0.05 g, of 10% palladium on carbon is used, and the mixture is hydrogenated at a pressure of about 30 to 60 psi, preferably 40 to 50 psi. The reaction is carried out at about 0 to 50 ° C, preferably at 25 ° C for about 24 to 72 hours, preferably about 42 hours. Alternatively, for hydrogenation, gasified tin (Ιί) can be used in ethanol and ethyl acetate. carry out. Normally, per mole compound -39-This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page), τ printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 517049 5. Description of the invention (37 objects 2? Use about 1 to 5 'preferably 3 to 4 moles of vaporized tin (η). The reaction is about 20 to 90 ° C, 60 to 70 more (: For about 24 to 72 hours, preferably about 24 to 48 hours. After hydrogenation with vaporized tin (π), the reaction mixture is cooled to the temperature of the garden, and with an inert solvent such as ethyl acetate Combination. Neutralize the reaction mixture by adding an appropriate base, such as sodium bicarbonate. Isolate the reaction product of any of the above routes by conventional methods, and perform the mixture on, for example, a dream stone gel with a suitable solvent such as Dichloromethane or its deer compound ', for example, 5 to 20% of methanol is dissolved in digas methane, and the technique of elution is eluted. Compound 23 is then treated to form alkylsulfonamide (compound 24). Here Compound 23 with an appropriate alkyl halide, such as chlorinated Based on a combination of inert organic bases such as Edian, digas methane containing a base such as triethylamine, etc. It is common to use about j to 3 per mole of compound 23, preferably 1.5 to 2 moles The alkane sulfone halide. The reaction is carried out at about · 10 to 5 CTC, preferably at 0 to 10 ° C for about 4 to 24 hours, preferably about 6 to 8 hours. For the reaction mixture, for example, by adding Sufficient amount of water, and the reaction mixture is warmed to the surrounding temperature and treated to hydrolyze the unreacted gasified alkylene group. Then the reaction mixture is quenched to a pH of about 1 by adding an appropriate acid such as a salt boat. i to 3 ′ is preferably pjj. The product (compound 24) is obtained as a solid and dried in a conventional manner. The compound 24 obtained from the above is treated to treat the 2-imidazoline moiety. Introduced here. Compound 24 is treated to form fluorenimide functionality. Compound 24 is suspended in an inert organic solvent such as dichloromethane, and about 1 to 4 per mole of compound 24, preferably 2 to 4 3 moles of ethanol is added and the reaction will be carried out 丨-<9 ♦ · (Please read the notes on the back first Refill this tribute) Order __ -40- 517049 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (38 compounds cooled to about -10 to 50 ° C, preferably about 0 to 1 ( rc. Pass an inorganic acid such as gaseous 4 anhydrous HC1 into the mixture to completely saturate the mixture, which takes about 20 to 60 (usually 25 to 35) minutes. Stir the reaction mixture for about 30 minutes to 5 hours, Preferable! To 2 hours, then raise the temperature to the Baoyuan temperature and stir the reaction mixture for 6 to 24 hours, preferably 10 to 12 hours. By evaporating the solvent and adding an inert organic solvent after evaporation, For example, dichloromethane gives compound 25. The imidazolinyl group is formed from compound 25 by adding about 1 to 2, preferably 2 to 15 moles of diaminoethane (ethylenediamine) per mole of compound 25. The reaction is about 20 to 50. (:, Preferably about 20 to 30.) (: at a temperature of about 4 to 24 hours in a suitable inert solvent such as alcohols such as methanol, under an inert gas such as nitrogen, argon, etc. It is completed in about 10 to 20 hours. The solvent is removed by evaporation, and then the reaction product is treated with a strong base such as ammonium hydroxide to produce salts. The resulting compound 26 is then obtained from various inert solvents such as methanol , Dichloromethane and the like. Alternatively, compound 26 can be obtained directly from the compound by treating it with ethylenediamine and fmethylaluminum (previously, Winter Blue et al.) Cardiogram G outlines a pathway for preparing compounds of formula ^ where a is r1s〇2NH_, _CHy or -0CH2, and ¥ is 2-imidazoline. Scheme Π ·

517049 A7 V. Description of the invention (,, V Ϊ r1s〇2n ^^, R7 ^ j R4 R5

R

, X

R5 Ts fs 28

, X-CN

Compound 24 was processed by the Consumer Standards Cooperative of the Central Bureau of Standards of Didi to convert cyano to aldehyde. This can be done, for example, by combining compound 24 with a suitable reducing agent such as DIBAL, triethyl lithium hydride and the like. Compound 24 is suspended in an inert organic solvent, such as an ether-based solvent such as diethyl ether, dimethoxyethane, dicrater, tetrachlorobutan, and the like. The reaction mixture is cooled to about -10 to 50 ° C, preferably about 10 to 10 ° C, and 24 to about 3 to 7, preferably 4 to 5 mols of DIBAL per mole of compound are added. The reaction mixture is stirred for about 30 minutes to 3 hours, preferably 1 to 2 hours, and then the excess DIBAL is destroyed by adding an excess of methanol or the like. The solvent is evaporated and the resulting product compound is "neutralized by adding an inert organic solvent such as ethyl acetate, and acids such as hydrochloric acid to a pH of about 1 to 2, preferably pH 1. The reaction product is suitably inert Extraction with a P organic solvent such as ethyl acetate, washing with a saturated salt solution such as saturated sodium chloride, and drying to obtain compound 27. Next, by dissolving compound 27 in an inert organic solvent such as alcohol, such as ethanol, methanol, and the like , And add 27 pairs per mole, about 0 per mol of compound-0 This paper size is applicable (read the precautions on the back before filling in this page)

517049 A7 B7 V. Description of the invention (40 Appropriate isocyanide of 1 to 1.5 mol, such as isocyanate, etc., by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Labor of the People's Republic of China, and later, 1 3 to 3, preferably 1 to 1.5 mol, are added as cyanide ions such as sodium cyanide, potassium potassium and the like, and the acid functionality of compound 27 is converted to monohydroimidazole (described below, Butch ( Buchi) et al.) The reaction mixture is stirred for about 6 to 24 hours under an inert gas such as nitrogen, argon, etc., preferably at a temperature ranging from about 30 ° C to about 30 ° C, preferably about lc. At 12 o'clock, the reaction mixture was passed through an oven and the dihydrozirconium product (compound 28) was dried. The desired 4-imidazole product (compound 29) was obtained from compound 28 and was obtained by treating it with ammonia. The reaction is usually completed in a sealed container. Compound 28 is suspended in about 10 to 20, preferably 10 to 15 mol per inert organic solvent such as alcohols, such as isopropyl alcohol, methanol, Ethanol and the like. The reaction mixture is at about 80 to 120 ° C, preferably about 90 to 100 ° C. Stirring is carried out at a temperature of about 3 to 8 hours, preferably about 4 to 6 hours. The reaction mixture is cooled to the surrounding temperature and the sealed container is opened. The solvent is removed by evaporation and the resulting product (compound 29 ] Purification by chromatography. Another approach to introduce 4-imidazolyl compounds where a is P ^ SOaNH-, X is {^ wide or -0CH2 ·, and γ is 4-imidazole, is summarized in Flow chart. Figure Η: Flow chart Η R4XI X-Br

R5 -43 · This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) (read the precautions on the back before filling in this page)

1T 517049 A7 B7 V. Description of the invention (41)

(Read the precautions on the back before you fill out this page.) The Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs printed this route, using conventional methods, such as reacting compound 2 j with the desertification clock (J · Am · Chetcu Soc. (1995) 21: 4903), and the compound 21 obtained above is converted into the bromide compound 30. Excessive strong tests such as n-alkyllithium such as n-butyllithium, and 2- (tertiary-butylmethazine) -Bu (N, N-dimethylaminosulfon §S group) · imidazole ( Nongjido Soc_Perkin Trans. I. (1990) 1645) (about 0.5 to 2.0, preferably 0.8 to 1.2 moles per 2 moles of compound) in a suitable inert organic solvent such as ethers such as tetrahydrofuran, diethyl ether , Dimethoxyethane, dioxane and the like. The above mixture is cooled to about -50 to -10 (rc, preferably at a temperature of about ° C, and Compound 30 is added. The reaction mixture is stirred for about 6 to 24 hours, preferably about 10 to 12 hours. During this period, the temperature is allowed to warm to the surrounding temperature. The resulting product (compound 31) is subjected to various extractions with an inert organic solvent, followed by brine, and then using a suitable solvent system, such as ethyl acetate / hexane, hexane Perform column chromatography on alkanes, etc. In a manner similar to that used in the above flow chart F to convert compound 22 to compound -44- This paper ruler National Standard of Finance (CNS) 7 ^ 7210X297 ^ 1 ----— __ Order • II1. 517049 A7 B7 V. Description of the Invention (Method of 42 23 'Treat compound 31 to convert its nitro group to amine of compound 32. The desired product (compound 33) is based on the formation of an alkylsulfonamido group During the period, it was obtained in a manner similar to that used to convert compound 23 to compound 24 in the above-mentioned scheme F. The protecting group in compound 32 was removed during the completion of the acid preparation. The imidyl group is introduced in which a is RiS〇2NH_ and X is -OCH2 · ′ And γ is a 4-imidazole compound of formula J, which is summarized in the flow diagram I:

Flowchart I

A ►

kTr

Tr

Tr 37

38 Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, compound 34 (a 3-nitrophenol) and reacting (1H-imidazol-4-yl) _methanol with trityl chloride (Tr) The prepared 〇-trityl 45- this paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) 517049 A7 __________ _______B7_ V. Description of the invention (43 ~) — &quot; ~~: 1H-imidazole · 4 · group) _methanol, deae (diethyl azide dicarboxylate) and deae (diethyl azide dicarboxylate) in a suitable inert organic solvent such as ethers such as tetrafuran, diethyl ether, dimethoxyethane, dizane and the like Combining in the presence of triphenylphosphine (Mitsunobu, Au_98i). The reaction is usually completed using 34 pairs of DEAE and 2 moles of triphenylphosphine per mole of compound. The reaction mixture is stirred at a temperature of about -10 to 60 ° C, preferably about 20 to 30 ° C, for about 1 to 72 hours, preferably about 2 to 24 hours. The reaction mixture is cooled to the surrounding temperature, The resulting product (Compound 35) was purified by chromatography. It was used to convert Compound 22 in a similar manner to Scheme F above. The compound method converts the nitro group in compound 35 to an amine group to obtain compound 36. Compound 37 is obtained by a method similar to that described in the above scheme F for converting compound 23 to compound 24. The desired product (compound 33) It is obtained by hydrolyzing the trityl group in compound 37 by a conventional method, for example, by treating with a dilute inorganic acid such as hydrochloric acid in the presence of an inert organic solvent such as acetonitrile. A method for preparing a compound of formula 1 in which A is κ ^ 〇2ΝΗ-, X is -NH-, and Υ is 2-mitulline.

Flowchart J (Please read the precautions on the back before filling out this page) One pack · 1T Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

N〇2 R5

46- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 517049 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 V. Description of the invention (44)

Compound 39 is treated under mild conditions to convert one of the nitro groups to the amine group of compound 40. Here, the compound is compounded with a mild reducing agent, such as sodium dithiosulfinate, ammonium sulfide, sodium sulfide and the like. The reaction is usually carried out in an aqueous organic solvent, such as an alcohol (methanol, ethanol, etc.) / Water mixture, where water can be present at 20 to 80% by volume. Compound 41 is obtained from compound 40 in a manner similar to that described in the above-mentioned scheme ρ for converting compound 23 to compound 24. In a manner similar to that described in the above-mentioned scheme F, for converting Compound 22 into Compound 23, the nitro group in Compound 41 is converted into an amine group to obtain Compound 42. The desired product (Compound 43) is obtained by treating Compound 42 with 2-chloroimidazoline, wherein 2 to 5 moles of 2 · chloroimidazoline and 1 mole of compound 42 are used in an inert organic solvent such as an alcohol Such as methanol, ethanol, isopropanol and the like. The reaction mixture was cooled to the surrounding temperature, and the resultant product (Compound 35) was purified by chromatography. As can be understood, the above flow chart j is mainly applicable to the preparation, and the above-47- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (21 × 297 mm) &quot; &quot; ~ — (Please read the first (Please fill in this page again)

45 517049 Α7 Β7 V. Description of the invention (Compounds in which R5 and R7 are Η and R4 and R6 are not Η. Another route to compounds in which R4 and R6 are not Η is shown in flowchart K. 〇2Ν,

Ν〇2 flowchart Κ

Ν〇2

Ν〇2

R

Ν〇2

Flowchart J (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy Treatment in tri-butanol (see, for example, Yamada et al., J. Am. Chem. Soc. (1912) 94.:6203) ^ to convert the carboxylic acid moiety to a third carbamate Compound 45. Hydrolysis of compound 45 to obtain compound 46 is accomplished by adding acids such as trifluoroacetic acid, hydrochloric acid, and the like (see, for example, Stahl et al., J. Org. Chem. ( 1978) 11: 2285). Compound 46 is reacted with tertiary-butyl nitrite in an inert solvent such as acetonitrile, tetrahydrofuran, etc. in the presence of vaporized copper (II) (see, eg, Doyle et al., J. Org. Chem. Π977) 11: 2426), while converting Compound 46 to the chlorine substituent of Compound 47. The remainder of the conversion of compound 4 7 into a 2-mibitrine derivative in this synthesis was completed as indicated by the above-mentioned flow chart J. 48- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) 517049 A7 B7 V. Description of the invention (46 In addition-to which R4 and R6 are not H, or medium ... and rule 7 are not η The pathways of the compounds are shown in Scheme L. R4 Family Diagram

R4

NHC-R38 II 〇

Ν〇2 νη2 (Read the precautions on the back before filling this page)

Flowchart, 1T Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Deacid-like acid is processed in a conventional way to process compound 48 to form amidine (compound 49). Acetic anhydride, propionate and other reactions. Compound 49 was then treated to introduce a nitro group as found in compound 50. Here, the compound pseudo and nitric acid are processed by a conventional method (〇1 ^ (1916) 49: 622). The amidine is hydrolyzed according to standard conditions, for example, an aqueous inorganic acid such as sulfuric acid, in the presence of alcohols such as methanol, ethanol, etc., to obtain compound 5j, which is then treated to remove the amine group, and compound 52 is obtained. Here, compound 5 [with nitros-49- 517049 A7 B7 47 5. Description of the invention (first-butanol, bismuth nitrosyl isoamyl, benzyl nitrite, etc.) are inert organic solvents, such as two Methylformamide, dioxane, tetrahydrofuran, etc., are combined according to conventional procedures (see, for example, Doyie et al.

Chem (1977) (&quot; · 3494). The conversion of compound 52 into the remaining residue of 2-imidazolinium in this synthesis was completed as indicated in the above flow chart]. Among them, R2 and R7 can form a compound of formula j having 2 to 3 atoms of an alkylene group or an alkenyl group in a Hong or Bu ring, which can be prepared through the following reaction scheme. For those compounds where 彳% and γ are 1 imidazoline, compound 53 and I ^ SC ^ V where V is halogen, and a strong base such as NaN (TMS) 2 (TMS = trimethylsilyl) ) Reacted in the presence of compound 54. The latter compound is converted into compound 55 in the presence of a reducing agent such as lithium aluminum hydride (LAh), lithium borohydride, and calcined-sulfide methyl complex. Compound 55 is treated with, for example, carbon tetrabromide and triphenylphosphine (ph3P) or phosphine bromide and pyridine to obtain compound 56, which is converted into cyanide ions such as sodium cyanide and potassium cyanide in the presence of Compound 57. Compound 58 can be produced from compound 57 by using the above scheme B. The reaction scheme is shown in scheme M. Flowchart M (Read the precautions on the back before filling in this page)

C-〇r4〇 NaN (TMS) 2 -► R5 r1so2v OR40

LAH R4

50 · This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 517049 A7 ------ B7 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Distillation

CBr4 Ph3P S, 〇2r1 f N ^^ \ ^ CH2Br NaCNUJ., S〇2r1 γ s〇 R &gt;, j ^ j | / CH2CN flow diagram B n! ^ I R6 57 kR5 56 .1 R4

For those compounds whose meaning is _NH_ and whose y is 2 · imidazole &amp;, the chemical compound 59 and ris02V in which V is a halogen are used, such as ν &amp; ν (τμ§) 2 ( TMS = trimethylsilyl) to give compound 60. The latter compound is converted into compound 61 in the presence of reducing agents such as hydrogen and platinum dioxide, hydrogen and palladium on carbon, iron in acetic acid, tin chloride (11), tin chloride (m), and the like. Compound 62 can be produced from compound 61 by using the above scheme 3. The reaction flow chart is shown in Flow chart n. Flowchart N

59

NaN (TMS) 2 ---] r1so2w so2r1 R4 H2, Pt〇2, \ R5 (Read the precautions on the back before filling this page)

s'〇2R1 『N, ^ k ^ NH2 flow chart d person I

62 61 51-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 A7 B7 V. Description of the invention r) For those compounds where X is -OCH2- and Y is 2-imidazoline, Compound 63 and K ^ 02ν in which V is halogen, in a strong base such as NaN (TMS) 2 (TMS ditrimethylsilyl), LiN (TMS) 2, LDA (lithium dipropionammonium lithium) LDA, NaH, etc. The compound is reacted in the presence of the compound to obtain compound 64. The latter compounds are hydrolyzed such as pyridine (Pyr) · hydrogen chloride (Grates et al., JACS (1963) 21: 1380), TMSI (Jung et al., 1 ^ (1977) 11: 3 761), BBi * 3, etc., converted to compound 65. Compound 66 can be prepared from compound 65 by treating with bromocyanomethane in the presence of a strong base such as NaN (TMS) 2, LiN (TMS) 2, LDA, NaH and the like. Compound 67 can be produced from compound # 66 by using Scheme B above. The reaction scheme is shown in Scheme 0. R41 is a low-order amino group such as methyl. Flow chart 〇 (Please read the notes on the back before filling this page) R4

64 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

R4

66 -52- The size of this paper applies to Chinese National Standard (CNS) A4 (210X297 mm) 517049 A7 B7 V. Description of the invention (50 so2r '0

According to the scheme P, a compound 1 in which Y is oxazoline or pyrazoline can be prepared. Formula J is used to prepare compound 70, which is combined with ciCH2CH2CNO to give compound 71. Compound 71 is cyclized by treatment, and 2-inyala ring in compound 72 is formed. This can be accomplished under conditions such as treatment with methyl fluoride and alumina in acetonitrile, or heating an aqueous solution of compound 71. This type of reaction is described in Wang et al., Bioorganic and Medicinal Chemistry (1994) 19:23 17 〇 This reaction is outlined in scheme p. Flowchart P

R5 nhcnh (ch2) 2ch2ci H R4 (Read the precautions on the back before filling in this page) · Installed-, -port Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economy R1S〇2

KF / AI2O3-^ ch3cn .ΛΛ

R5 21 72 For compounds where A is R3R6 () NS〇2NR2_a χ is _cti2- or -〇CH2-, the following illustrative flow chart R can be used. The amine group located in the precursor compound and an appropriate alkali metal cyanate, such as cyanate _ in water acid solution 53- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 A7 B7 (51 reaction in the liquid to form a ureido group. Then follow the same procedure as in Flowchart B to convert the cyano group to fluorenimide functionality and condense it with 1,2-diaminoethane to form 2- Imidazoline. Flow chart RΛ. P4

KOCN H2N ^ H0Ac / H20 17

• CN R37〇H kR5 77 (Read the precautions on the back before filling in this page)

37 H2NCH2CH2NH2 h2n R / R4 .4] -R5 78 29 The following illustrative scheme S can be used to synthesize the present invention where A is CH3S02NH, X is -OCH2-, Y is 2-imidazoline, R4 is CH3, and R5 is Η Compounds where R6 is fluorene and R7 is halo (preferably chloro, bromo or iodo)

Flowchart S Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

/ CN ch3

OH KOtBu, THF, DMF

TsO CN

PhMe

/ CN HC1 -►

EtOH, CH2C12 -54-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 517049 A7 B7 V. Description of invention f2

CH3so2N

__ch3oh 2) iPr0H / H20 recrystallized ch3so2n

〇 ^ &lt;: N-HC1 Printed R7 R7 by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs The desired product is via 4-halo-3-amino-o-cresol, (2-methyl-3-amine The methyl-4- is obtained from phenoxy) acetonitrile and N · (6-fluorenylcyanomethoxy-2-methylphenyl) methanesulfonamide intermediate. In order to obtain 4-dentate-3-amino-o-toluene intermediates, a positive halogen (eg, gas) source was used, such as] Succinimide, melamine, trichloroisocyanuric acid, and hypochlorous acid. Tertiary-butyl esters, thiosulfonium gas, and the like, the best is N-chlorosuccinimide, which completes the halogenation of 3-amino-o-cresol. Halogenation is based on anhydrous strong acids, such as formic acid, sulfuric acid, trifluoroacetic acid, etc., the best is methanesulfonic acid, at about 0-50 ° C, the best is 5-12 C temperature. The dentification reaction yields a desired 4-ammonio-3-amino group-o-cresol, isomeric fluorenylamino-o-cresol, and a small amount of 4,6 · monoamyl-3 · amino -O-Benzene test mixture. After the reaction mixture is warmed up (about 50-8 0 'optimally about 5 0 _ 60 ° C), the solution is tested with hydrogen hydroxide in solution' and the desired intermediate is separated by filtration. . This can be done by adding dilute ammonium hydroxide to the reaction mixture, or by adding the reaction mixture to dilute ammonium hydroxide, or (preferably) by adding the reaction mixture to water 'and then adding concentrated hydroxide Press join. In any case, the exothermic nature of dilution and acid neutralization will cause the mixture to heat up significantly. The 4_fluorenyl isomer is highly crystalline and is significantly less soluble than other products at elevated temperatures, enabling selective crystallization of the desired intermediate in a purified state (4_fluorenyl-3-amino-o-methyl phenol). If necessary, it can be from water-containing isopropanol or -55- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (read the precautions on the back before filling this page) Staff of the Central Bureau of Standards of the Ministry of Economic Affairs Printed by the Consumer Cooperative 517049 A7 ________ ^ 5. Description of the Invention (53) ~~ ^ ~ Toluene recrystallizes, or (preferably) by heating the intermediate to boiling in water and allowing the mixture to cool to room temperature, where The purified intermediate was then separated by filtration and further purification was completed. The purified 4 · fluorenyl_3_amino-o-cresol intermediate is then dissolved in a dipolar non-polar intermediate by first dissolving the toluene intermediate with an alkali metal alkoxide, preferably potassium dibutoxide. A protic solvent, such as a solution of tetrahydrofuran, N, N • dimethylformamidine, N-methylpyrrolidone, dimethylsulfinium, or a mixture thereof, is processed at a temperature of about 20 C, and Conversion to (2-methylamino-4-_phenoxy) acetonitrile intermediate. The mixture is partitioned between an organic phase (e.g. toluene or ethyl acetate) and an aqueous phase, and the aqueous phase is extracted with an organic solvent such as toluene or ethyl acetate. The combined organics were extracted with dilute NaOH and concentrated with water. The (2-methyl, 3-amino-4-_phenoxy) acetonitrile intermediate was then converted to N- (6_selfyl-3-cyanomethoxy_2_methylphenyl) methanesulfonium amine. Methanesulfonium is added to a solution of (2-methyl-3-amino-4-phenoxy) acetonitrile in a solvent such as toluene or ethyl acetate, and the mixture is heated to about 4 (rc.). Pyridoxine was added slowly. The resulting solution was cooled and stirred. The mixture was then partitioned between 1N hydrogen acid and a mixture containing ethyl acetate and tetrahydrofuran. The organic phase was washed with water and concentrated, resulting in N -(6-Electro-3-cyanomethoxy-2-methylphenyl) methanesulfonamide. This crystalline intermediate is collected, washed with an organic solvent such as toluene or ethyl acetate, and dried. If necessary This material was recrystallized from isopropanol. Gaseous gaseous hydrogen gas was passed into N_ (6__yl-3-cyanomethoxy-2_methylphenyl). Suspension of ethanol mixture -56- Exhaust, common, and Zhang scales Common Chinese National Standard (CNS) Α4 Specification (21〇χΜ7mm (Please read the first notice on the back of the page before filling in this page)

517049 A7 B7 V. Description of the invention (54) Xin Zhong, keep the temperature below about 15. (:. The resulting mixture is stirred at a surrounding temperature, during which the first hydrogenated sulfonium imidate is precipitated. The excess hydrogenated gas is removed from the reaction vessel, and the formed The slurry was completely dissolved by adding methanol. This solution was then added to the solution of ethylene diamine in methanol &amp; to keep the temperature below 25.0. The desired product salts, hydrogen were precipitated from the reaction mixture. κΝ_ [6_ 南基 _3_ (4,5-diimidazol_2 · yl-methoxy) -2-methylphenyl] sulfonamidine and purified by conventional techniques. If necessary, This material is recrystallized from isopropanol / water. The separation spot is ideally suitable for any separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, and thin layer chromatography. The separation and purification of the compounds and intermediates described in the text can be carried out by using techniques, thick chromatography, preparative low or high pressure liquid chromatography, or a combination of these procedures. Special instructions for suitable separation and purification procedures can be Reference is made to the following examples herein. However, other equivalent separations or purifications can of course be used. A series of preferred specific examples of compounds, a series of preferred compounds according to the present invention, including the compound represented by Formula 3, or a pharmaceutically acceptable salt thereof. ^ (Read the precautions on the back before filling (This page) Employee Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs, India

Where Y is 2-Weijun p Lin, and -57- This paper standard it financial standard (CNS) A4 specifications (21 heart 297 clever -----------. _ 517049 ΑΊ B7 V. Description of the invention (55

R 19

R 20

R 21 Η Η Η Η Η βΗΗ, imidazolidine-2-ylamino) -phenyl] methanesulfonamide CH3 h ch3 η η imidazolidine-2-ylamino) -2-methyl-phenyl] CH3 η η η H CH3 oxazidin-2-ylamino) -2-methyl-phenyl] formamidine

CH Η H CH3 H Cl (N45-qi-3- (imidazolidin-2-ylamino) -2-methyl-phenyl] formamidine) CH3 Η Η Η Cl Η imidazolidine-2_ Amino group) -phenyl] methanesulfonate to 丄 H CH3 H Br CHc ---- --------, · ---- (Please read the precautions on the back before filling this page) Printed by the Consumer Bureau of the Standards Bureau (N- [5-Bromo_3 Phenylimidazolidine_2-ylamino) -2-methyl-phenyl] methylenepyrazine) _ CH3 h ch3 h ch3 η 咮Amidazin-2-ylamino) -2,5-dimethyl-benzyl j_ysulfonamide 1 CH3 η hh och3 η H [3 "(imidazolidin-2-ylamino) -5-methoxy -Phenyl] methanesulfonylamine) CH3 Η CH3 η CH (CH3) 2 η (N- [3- (imidazolidin-2-ylamino) -5-isopropyl-2-methyl-benzene [Methyl] methanesulfonamide) ___ ch3 hhh ch3 ch3 (N- [5- (imidazolidine-2-ylamino) -2,3-dimethyl-phenyl] methanesulfonamide) 58 Paper size Applicable to China National Standard (CNS) A4 specification (210X297 mm)

, Invention description (56 A7 B7

3 LJ ^ η Η H Cl Η &quot; ^ 米 Junidine J CH3-: (Η η CH3 Η aminoamino) -3-dimethyl-phenyl] methanesulfonamide) 1 shot 3 it (NH ch3 η η ch3 [3_ (Tendamidine-2-ylamino) · 2,6-dimethyl · phenyl] methanesulfonamide) • 2-ylamino) -phenyl] methanesulfonamide) · __ -ym 'Person ·, 1 Preferred compounds according to the present invention, including the _ thing' represented by Formula 4 or a pharmaceutically acceptable salt thereof: R23 R24

For 2-Mi Panlin, R22

ch3 η η (N- [3- (4,5-dihydro · 1Η-imidazol-2-ylmethyl) · 2-methyl-phenyl] methanesulfonamide) (Please read the precautions on the back first (Fill in this page) One Pei--Order 1 · Economics, that is printed by CH, 合作 Η Η H CH3 (Ν_ [5- (4,5-dihydro_ιη-imidazole-2-yl) ) -2-methyl-phenyl] methanesulfonamide) CH, Η Η H Cl CH3 (N- [3-chloro-5- (4,5 · dihydro-1H-imidazol-2-ylmethyl) ) -2-Methyl-phenyl] -59 This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 517049 Α7 B7 V. Description of the invention (57) Methanesulfonamide) __ CH3 Η Η Η Br CH3 (] ^-[3-bromo_5- (4,5-dihydro-1H-imidazol-2-ylmethyl) -2-methyl-phenyl] methanesulfonamide) _ ch3 Η Η hh och3 (N- [5- (4,5 -dimur · 1Η-Mijun-2 -ylmethyl) 7 2 -methoxy-phenyl] methanesulfonamide) ____ ch3 η η η η η (Ν_ [ 3 '(4,5-dihydro-1Η-imidazole, 2-ylmethyl) · phenyl] methanesulfonamide) ch3 η Η hh oh (N- [5- (4,5-dihydro-1Η_ Imidazol-2-ylmethyl) -2-hydroxy · phenyl] methanesulfonamide) ______ CH3 Η Η F Η Η (N- [3- (4,5-dihydro-1Η-imidazole-2_yl) base -4 · Fluoro-phenyl] methanesulfonamide) ___ ch3 ch3 ch3 η η η (N- [3- (4,5_dihydro-1Η-imidazol-2-ylmethyl) · 2-methyl- Phenyl] · # Ν! _ Methyl-methanesulfonamide) ______ ch3 Η Cl η η η Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) (Ν- [ 2-gas-3_ (4,5-dihydro · 1Η_imidazol-2-ylmethyl) _phenyl] methanesulfonamide) _ ch3 h c6h5 η η η

I (N- [6- (4,5-dihydro · 1Η-imidazol-2-ylmethyl) -biphenyl-2-yl] methanesulfonamide) -60- This paper size applies to Chinese national standards (CNS ) A4 specification (210X 297 mm) 5. A7 B7 Description of invention po (NΆ (3Η π, Bujun-4-ylmethyl) -2_methyl-fluorenyl] methanesulfonamide), 歹] Preferred compounds according to the present invention 'including those represented by Formula 5' or their pharmaceutically acceptable salts:

Lin, Ministry of Economic Affairs ^^ Standards Bureau Employees' Cooperative Cooperative Seal 1 and r2CZ ^ (N · 3 Η Η Η Η Η ΗMijun-2-yl 曱 oxy) phenyl] methanesulfonamide) CHs Η Η Η Η F ( Ν [5 · (4,5-dihydro · 1Η-imidazole_2-ylmethoxy) _2_fluoro-phenylsulfonamide) ------ CH3 H wu HHH η CH3 (N- [5 -(4,5-dihydro-iH-imidazol-2-ylmethoxy) _2-methyl · phenyl] methanefluorenamine)-~ 丄 ---------- CH3 η Η Η η Cl (Ν- [5- (4,5- 一 风 -1Η_imito-2_ylmethoxy) _2_chloro-phenyl] methanamine)

32 ► 33 C2H5 Η Η Η ιι (ethanesulfonic acid [3- (4,5_dihydro-1Η-imidazole-2 · ylmethoxy) _phenyl] methyl] -63-This paper size applies to Chinese national standards (CNS) A4 specification (210 × 297 mm) 517049 A7 B7 V. Description of the invention (61) sulfonamide) ____ c3h7 η η η η η (propane-1-sulfonic acid [3- (4,5-difluorene-1Η- Imidazol-2-ylmethoxy) -phenyl] formamic acid amine) ___ ^ _ c6h5 η η η η η (N- [3- (4,5-dihydro · 1Η · imidazolylmethoxy)- Phenyl] benzenesulfonamide) ch3 η η η η οη (Ν- [5_ (4,5-dihydro_1Η-imidazol-2-ylmethoxy) -2-hydroxy · phenyl] methanesulfonamide ) _____ ch3 h ch3 η η η (N_ [3- (4,5 -diwind-1Η-味 峻 -2 -ylmethoxy) 2 -methyl-epoxy] methanesulfonamide) _ ch3 hh ch3 η η (N- [3- (4,5-dihydro-1H-imidazol-2-ylmethoxy) -4-methyl-phenyl] methanesulfonamide) ___ ch3 hh ch3 h ch3 (N- [3 · (4,5-dihydro_1H-imidazol-2-ylmethoxy) -2,4 · dimethyl · phenyl 1 methanesulfonamide) ___ Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling out this page) CHa H CH3 Η Η CH3 (N- [3- (4,5-dihydro_1 -Imidazol-2-ylmethoxy) -2,6_dimethyl-phenyl] methanesulfonamide) _______ ch3 h ch3 η η Cl (N_ [6 -milk 3- (4,5 ^ · 二Rat_1Η -Weijun -2 -methylmethyl milk) -2 -methyl-phenyl] methanesulfonamide) -64- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 517049 A7 —__________ 5. Explanation of the invention (63)-1] ^-5-Fluoro-5- (111-imidazole-4 (5) -ylmethoxy) -phenyl 1methanesulfonamide) CH3 η η η Η Cl Chlorine -5- (1 fluorene-imidazole-4 (5) -ylmethoxy) -phenyl 1 methanesulfonylamine) ch3 h ch3 η Η cl (N- [6-chloro-3- (3Η-imidazole-4) (5) -Methoxy) -2-methyl-phenyl] methanesulfonate_ch3 hhhh ch3 0 ^ [2-methyl-5- (111-imidazole-4 (5) _ylmethoxy)- Phenyl] methanesulfonamide) Preferred compounds also include the following compounds, or equivalent free-state bases, and their pharmaceutically acceptable salts: (Please read the precautions on the back before filling out this page) # 装 · H 1 on CH3 Η ch3s〇2i ^ l

N- [2-methyl-3- (endazazolin-2-ylamino) -phenyl] methanesulfonamide; surface Φ CH3 \ N II / 〇

Orc

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ch3

• HCI hydrochloride Ν, Ν · dimethyl_N,-[3- (4,5 -dihydro-1H-imidazol-2-ylmethoxy) -phenyl] sulfonaminium diamine; 66-benzyl Paper size applies to China National Standard (CNS) A4 (210X297 mm) 517049 A7 B7 5

, Description of the invention (64 where Me = CH3

• HCI N-Methanesulfonyl-6- (4,5-dihydro-1H-imidazole · 2-ylmethyl) indole; *

Where Me = CH3 hydrogenated N-methanesulfonyl-6- (imidazolidine-2-ylaminoxindole; (read the precautions on the back before filling this page)

Where Me = CH3 years old * Fluorinated 6- (Tamiami-2-ylamino) 4 丨 Homo-1-continuous acid dimethylamidamine; printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs cw S〇2H- Pr where Pr = propyl sulfonamide-2 -ylamino- [1- (propyl-1-continyl) _ΐΗ-θ 丨 voc-6-yl] · amine;

ΝΗ 67 This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm)

517049 A7 B7 V. Description of the invention (65) Among which Ms di S02CH3 6-(4,5 -dirat-1Η-Weijun-2 -methylmethoxy) -1-methyl hordenyl-1Η-4 丨 p flower ;

Br ms · η〇Ι where Ms = S02CH3 imimidazol-2-yl- (1-methanesulfonyl-3-bromo-1H-carboxol-6-yl) -amine; ch3

Rat gasification and elongation are also · 2 · radical-(1- -continued S &amp; radical -3 -methyl-1---p-6 _-)-amine; (read the precautions on the back before filling in this page)

Among them Ms 2 S02CH3 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, Hydroxylimidazol-2-yl- (1-methylsulfonyl-3-chloro-1H · indol-6-yl) · amine; and

Among them Ms II S02CH3 -68- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (Ming) Hydrogenated imidazolidine- 2-yl- (1-methylpyridinyl-3-cyano-1H-pyridin-6-yl) ▲ amine. Another series of particularly preferred compounds include ... (N- [3_ (4,5-dihydro_1H_imidazolylmethoxy) -phenyl] methanesulfonamide); (N- [6-Ga-3 -(4,5-dihydro-1H-imidazol-2-ylmethoxy) -2-methyl-phenyl] methanesulfonamide); (N_ [6_bromo_3_ (4,5 ”dihydro -1H-imidazole-2_ylmethoxy) _2_methyl-phenyl] methanesulfonamide); N- [5- (4,4 -Two wind-1H -Weijun · 2-ylmethyl lactyl group ) -2-Gas-phenyl] methane amine; N- [3τ (4,5-dihydro_1H-imidazol-2-ylmethoxy) -2-methyl-phenylhydrazine] methanesulfonamide ; N- [3- (imidazolidin-?-Ylamino) -2-methyl-phenyl] methanesulfonamide; N- [5- (4,5-dihydro-1H-imidazolylmethyl) ) -2-methyl-phenyl] methanesulfonamide; N- [2-fluoro-5- (1fluorene-weijun-4 (5) -ylmethoxy) -phenyl] methanesulfonamide; hydrogen N, N_dimethyl-N,-[3_ (4,5_dihydro_1H-imidazol-2-ylmethoxy) -phenyl] sulfonaminium diamine; (3-Ga-1-methyl Sulfonyl-1H-pyridin-6-yl) -imidazolidin-2-yl-amine; or a pharmaceutically acceptable salt thereof. Preferred Process In summary, an illustrative compound represented by Formula 1 'It was prepared according to the following final steps: 1. For the preparation where A is R ^ SCbNH · X is -CH2- or -OCH2-, -69 _ This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page) ¾ Order · 517049 A7 V. Description of the invention (67 B7, a method of the compound of formula 1 in which γ is 2-imidazoline, which includes a person with the formula:

R5

, oc2h5 NH 2 · Alternatively, a method for preparing a compound of formula 1 in which A is, X is -CHy 'and γ is renimidazole, comprising a compound of formula:

Reacts with ammonia. 3. Alternatively, a method for preparing a compound of formula 1 wherein a is F ^ SC ^ NH-, X is -CH2, or -OCH2-, and Y is 4-imidazole, comprising a compound of formula : S02N (CH3) 2 4 tbdms Printed by the Consumer Cooperative of the Central Standards Bureau of Didi Ministry

Reacts with dilute mineral acids. 4. Alternatively, a method for preparing a compound of formula 1 wherein A is R ^ SC ^ NH-, X is · OCH2-, and y is 4-midwa 'comprises a compound of formula: -70 -(Please read the notes on the back before filling this page)

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 A7 B7 V. Description of invention (68) V fJs person ‘Μ

Ν, kTr

I • R5 R6 reacts with a dilute inorganic acid such as hydrochloric acid in an inert organic solvent such as acetonitrile 5. Alternatively, a method for the preparation of a compound of formula 1 where -NH-Y is 2-Mijunlin Contains the transformation of the following

ΝΗο R5 reacts with 2-chloroamidol. 6. Alternatively, a method for preparing a compound of formula i wherein 2 and 3 atoms of an alkylene group or an alkenyl group in a 5_ or 6-membered ring can be formed together with Han 7 and comprises Compound of the formula: R4, ch2cn (Please read the notes on the back before filling this page) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

SO2R1 VI and R5 react to convert the cyano group to fluorenimide functionality and condense it with i, 2-diaminoethane to form 2-imidazoline group. 7. · Alternatively, a method for preparing a compound of formula 1 in which 乂 is _NH- and γ is 2-micron, including a compound of the following formula: 71-This paper is scaled to Chinese national standards ( CNS) A4 specification (210X297 mm) 517049 A7 —B7 --------- *: ---------_ V. Description of the invention (69)

It reacts with 2-ylimidazoline to directly produce the desired compound. 8. Alternatively, a method for preparing a compound of formula 1 wherein X is -0CH2- and Υ is 2-imidoline, comprising a compound of formula:

The 1,2, -diaminoethyl: fe reaction 'forms a 2-weijun plinyl group. 9. Alternatively, a method for preparing a compound of formula 1 in which X is and γ is 2. oxazoline, comprising a compound of formula:

Ο

II NHCNH (CH2) 2CH2CI R5 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -------- · Installation— (Please read the precautions on the back before filling this page) with potassium fluoride and alumina in acetonitrile Reaction, or heating the aqueous solution of compound 71. 10. Alternatively, a method for preparing a compound of formula 1 in which A is Risc ^ NH-, X is -CH2_ or -OCHr, and Y is 2-imidazoline, comprising a compound of formula: -72 -This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 517049 A7 B7 V. Description of the invention (7〇) H R4

X-CN R5 reacts with ethylenediamine and trimethylaluminum. The present invention also includes intermediates having the following molecular formula as described above

(Please read the notes on the back before filling this page)

R5 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

And its salts, where X is -CH2- or -OCH2-, and R1, R4, R5, R6 and R7 are as defined in item 1 of the patent application park;

N and its salts, where X is -CH2-, and R1, R4, R5, R6, and R7 are as defined in item 1 of the patent application park;

S〇2N (CH3) 2 N ^ / TBDMS x- / v ll

N R5 and its salts, wherein X is -CH2- or _OCH2, and R4, R5, R6, and R. It is as defined in item 1 of the scope of patent application; -73- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm)

NH2 R5 517049 A7 B7 V. Description of the invention (71 H R4

Tr and its salts, wherein R1, R4, R5, R6, and R7 are as defined in the first scope of the patent application; R4, R5, R6, and R7 are as defined in the first scope of the patent application; ( (Please read the notes on the back before filling out this page)

And its salts, as defined in R1; R4, R5, and R6 are as described in the scope of patent application No. 1

nh2 R5 The members of the Central Standards Bureau of the Ministry of Economic Affairs and the Consumer Cooperatives printed f and its salts, of which R1, R4, R5, and R6 are as defined in item i of the patent application scope; CNS) A4 specification (210X297 mm) 517049 A7 B7 V. Description of the invention (72

OCH2CN and its salts, which are defined in R1 and f; R5 and R6 are the same as those in the patent application park

0 II nhcnh (ch2) 2ch2ci R5 (Please read the notice on the back xi before filling out this page, &gt; 5i clothing 'and its salts, as defined by R4; R5, R6, and R7 are as item i of the scope of patent application in

-Subscription- The printed matter of employees' cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and its salts, where X is -CH2j-〇CH2-, and R4, R5, r6, and r7 are as defined in item 1 of the scope of patent application. Salts of the compound of the present invention The compound of formula 1 can be converted into a corresponding acid addition salt by the effect of the presence of a third-order nitrogen atom. The conversion is by using at least one stoichiometrically appropriate acid, such as hydrogen acid, hydrobromic acid, sulfuric acid, nitric acid, transacid, etc., and organic acids such as -75- This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) 517049 A7 B7 V. Description of the invention (73) Acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, Tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-fluorenic acid, salicylic acid, etc. Typically, the free base is dissolved in an inert solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, etc., and an acid added in a similar solvent. The reaction is maintained at a temperature of about 0 to 50.6. The resulting salts precipitate spontaneously or can be taken out of solution with less polar solvents. The acid addition salt of the compound can be converted into the corresponding base by treating it with at least one stoichiometrically appropriate acid, such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like. Uses and Dosage: Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Therefore, the compound of formula 1 and its pharmaceutically acceptable acid addition salts have been found Available pharmacological properties', in particular, have been shown in standard laboratory tests as a selective avalin 1A / 1L-adrenergic receptor activator. Thus, these compounds and pharmaceutically acceptable compositions containing them can be used to modulate physiological phenomena associated with Aval 1A / 1L_adrenergic receptor activators, such as the treatment of urinary incontinence (blood pressure in mammals No harmful side effects), nasal congestion, abnormal erections, depression, anxiety, dementia, aging, Alzheimer's disease, lack of attention and discrimination, and eating disorders such as obesity, bulimia and anorexia. The test is used to identify the general strategy of Ava 1A / 1L-adrenergic receptor activators: -76- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 517049 kl _________B7 V. Description of the invention ( 74) ^ Rabbit in vitro-For the efficacy of avar iA / 1L-adrenergic receptor activator, isolated rabbit bladder headline tablets (Avar 1A / 1L- Epinephrine receptor), and the contractile efficacy and relative internal activity of isolated rat aortic rings (Ava 1D-adrenergic receptor) were determined as described in the examples below. In vivo: Next, the in vivo evaluation of the standard and novel compounds that selectively shrink the bladder neck strips of rabbits in anesthetized female mini-pigs will be analyzed for urethral activity related to diastolic blood pressure. D will be anesthetized Compounds with the desired activity in pigs are measured in a conscious female minipig by measuring diastolic blood pressure with a telemeter, and measuring urinary urinary tension using a tensiometer converter, as described in the examples below. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of General Dosing and Economics (please read the precautions on the back before filling this page). In the application of the compound of the present invention to the treatment of the above disease states, any ator-adrenergic receptor activator can be used They have been administered in a beam form for the active compounds and salts described herein. Any pharmaceutically acceptable mode of administration can be used (whether it is enteral or parenteral) and the dosage form can include any suitable solid, semi-solid, liquid, evaporated, or gaseous dosage form, such as a tablet, Suppositories, pills, capsules, powders, liquids, solutions, solutions, suspensions, emulsions, sprays, sprays, etc. are preferably in unit dosage form suitable for single or multiple exact dose administration, or in The compounds are administered chronically at a predetermined rate, in a sustained or controlled release dosage form. Although it can be said to be used for treatment, the compounds of the present invention can be processed without processing. -77 · $ Paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 5. Description of the invention (75) Chemical compound administration In general, it is preferred that the compound be expressed as an active ingredient present in a pharmaceutical composition or formulation. The total amount of active compound administered depends, of course, on the condition being treated, the individual being treated, the severity of the disease, the form of administration, and the judgment of the attending physician, pharmacy professional, or veterinarian. However, the effective dose is typically in the range of 0.15 to 1.5 mg / kg / day, and more preferably in the range of 0.35 to 0.70 mg / kg / day. For an average human of 70 kg, the total amount is 10 to 100 mg per day, preferably 25 to 50 g / day. The invention therefore further provides, comprising a compound of the invention or a pharmaceutically acceptable salt or derivative, and one or more pharmaceutically acceptable carriers and (if necessary) other therapeutic and / or prophylactic ingredients. The carrier must be "acceptable" insofar as it is compatible with the other ingredients in the composition or formulation and is not harmful to its excipients. These compositions will typically include customary pharmaceutically acceptable carriers or excipients, and active compounds of Formula 1 or pharmaceutically acceptable salts thereof, and may additionally include other pharmaceutical agents, pharmaceutical agents, carriers , Adjuvants, etc. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page)

Jm pharmaceutical compositions or formulations include those suitable for oral nasal, pulmonary, topical (including buccal and sublingual), rectal, vaginal, or parenteral (including intraspinal, intraarterial, intramuscular) , Subcutaneous marginal injection, and intravenous), or in a form suitable for administration by inhalation or insufflation. Therefore, the compounds of the present invention can be placed in the form of pharmaceutical compositions with conventional adjuvants, carriers or diluents Or its unit dose, and in this form can be used as solids such as tablets or filled capsules, or liquids such as solutions, suspensions, liquids, chitosan, or capsules filled in the same dosage form (street for oral use) , -78-

517049 A7 B7 Printed by the Consumers' Cooperative of the Central Bureau of quasi-branch of the Ministry of Economic Affairs 5. Description of the invention (76) In the form of suppositories for rectal administration, or as sterile injectable solutions for parenteral (including subcutaneous) . These pharmaceutical compositions and their rare dosage forms may contain conventional ingredients that are present in the known portion with or without other active compounds or main ingredients, and these unit dosage forms may contain any suitable and effective amount of An equivalent amount of active ingredient is used in the desired daily dosage range. Thus, a formulation containing one (1) g of active ingredient or (more broadly) 0 to 01 to one hundred (100) mg per tablet is a suitable representative unit dosage form. The compounds of this invention can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain the compound of the present invention as an active ingredient, or a pharmaceutically acceptable salt of the compound of the present invention. Solid form preparations include powders, tablets, pills, capsules, capsules, test agents, and dispersible granules. The solid carrier can be one or more substances which can act as diluents, flavoring agents, stabilizers, lubricants, suspending agents, adhesives, preservatives, tablet disintegrating agents, or encapsulating substances. In powders, the carrier is a uniformly finely divided solid containing a mixture of uniformly finely divided active components. For oral administration, the active ingredient is mixed with a carrier having the required adhesive capacity in a suitable portion and shaped into the desired shape and size. The powders and tablets preferably contain from 0.5% to 95% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugars, grape bran, sugar cane, lactose, pectin, dextrin, starch, gelatin, mannitol, cellulose, methyl cellulose, and carboxymethyl fiber Sodium Sulfate, Sodium Saccharin, Cross-linked Carboxymethyl Cellulose _____ · 79 Miscellaneous Paper ^^ Uses Chinese Standard (CNS) A4 Specification (210X297 mm) — '' — '' — _ (Please read the back (Please fill in this page for attention)

1T.Jm 517049 A7 B7 V. Description of the invention (77) (Please read the notes on the back before filling this page) Sodium, low melting wax, cocoa butter, etc. The term "formulation" is intended to include formulations containing the active compound and a sealing substance as a carrier for capsules in which the active ingredient (with or without a carrier) is provided in a carrier (and therefore associated with it), . Similarly, capsules and lozenge tablets are also included. Tablets, powders, capsules, pills, capsules, and lozenge tablets can be used as solid forms suitable for oral administration. For the preparation of suppositories, a low-melting wax such as a fatty acid-containing glycerol or cocoa butter mixture is first dissolved, and the active composition is dispersed therein by stirring. The dissolved homogeneous mixture is then poured into a convenient-sized mold, allowed to cool, and thereby gjized. Polyalkanediols such as polypropylene glycol can also be used as a carrier. Formulations suitable for vaginal administration can be presented and contain, in addition to the active ingredient, a uterine condom, tampon, cream, gel, ointment, foam or spray, and a carrier known to be suitable in the art. Liquid form preparations include solutions, suspensions, and emulsions; suitable carriers include &apos; for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs The compound according to the invention can therefore be formulated for parenteral administration (for example, by injection, such as bolus injection or continuous perfusion), and can be presented in safety Information, pre-filled syringes, small volume perfusion devices, or unit dosage forms in multi-dose containers containing added preservatives. These compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous formulations, and may contain formulatory agents such as suspensions, stabilizers, and / or dispersants. Alternatively, the active ingredient can be aseptically isolated -80- This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) 517049 kl Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Note (78) ~ Sterilized solids' or powders obtained by drying from solution, which are combined with a suitable carrier, such as sterilized, pyrogen-free water, before use. Aqueous solutions suitable for oral use can be made by dissolving the active ingredients in water, and if necessary, adding suitable coloring agents, flavoring agents, stabilizers, and thickeners. Aqueous suspensions suitable for oral use can be composed of a uniformly subdivided active composition with viscous substances such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents Suspended in water. Also included are solid form preparations which are intended to be converted to liquid form preparations for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. These formulations may contain, in addition to the active ingredients, colorants, flavoring agents, stabilizers, buffering agents, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like. For topical administration to the skin, the compound according to the invention can be formulated as an ointment, cream, or lotion, or as a transdermal patch. Ointments and creams can be prepared, for example, with an aqueous or oily substrate with the addition of suitable thickeners and / or gelling agents. Lotions can be prepared from aqueous or oily substrates, and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. Formulations suitable for topical administration in the oral cavity include diamond lozenges containing active agents stored in flavoured substrates, usually sucrose and gum arabic or tragacanth; and inert substrates such as gelatin and glycerol, Or oral tablets of sucrose and the active ingredients in gum arabic; You contain active mouthwash in a suitable liquid carrier. -81-This paper size is in accordance with Chinese National Standard (CNS) A4 (21 〇 × 297 mm) ί Please read the notes on the back before filling in this page j. ¾ clothes · order · d 517049 A7 __ B7 Central Ministry of Economic Affairs Printed by the Bureau of Standards Consumer Cooperatives V. Description of the Invention (79) The solution, emulsion, or suspension is directly applied to the nasal cavity by conventional methods, such as a dropper, drop meter or sprayer. The tincture can be provided in single or multiple doses. In the latter case, this can be achieved by administering an appropriate, predetermined volume of solution or suspension to the patient. In the case of sprayers, this can be achieved, for example, by metering an automated spray pump. Suitable liquid media include water, propylene glycol, and other pharmaceutically acceptable alcohols, and sesame or peanut oil, and other pharmaceutically acceptable vegetable oils. Generally, the active compound is administered as an aqueous spray having a concentration of 0.001 to 10, preferably 0.025 to 0.10%. Dosing for respiration can also be accomplished by means of aerosol, where the active ingredient is present in a substance such as chlorofluorocarbon (CFC), such as digas difluoromethane, diratyl monofluoromethane or digas. Tetrafluoroethane, carbon dioxide, or other suitable gases are provided in pressurized packages of suitable propellants. The aerosol may also conveniently contain a surfactant such as lecithin. The dose can be controlled by limiting the metering valve. Alternatively, the active ingredient may be a dry powder, such as a powder mixture of the compound in a suitable powder substrate, such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose, and polyvinylpyrrolidine (pVP) Provided. Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in a unit-measurement form, for example, in a gelatin process or capsule or cartridge, or in a blister pack that is administered as a western medicine from its starting powder. In formulations intended for administration of respiratory tadpoles, including nasal formulations, the compound will typically have a small particle size, such as a 5 micron digit or less. This -82- This paper size applies to Chinese National Standard (CNS) A4 specifications (2 丨 〇 &gt; &lt; 297 mm) (Please read the precautions on the back before filling out this page} • Binding-Order d A7 V. Invention Note (80 Printed by Hezhu Co., Ltd., employee of the Central Bureau of Standards, Ministry of Economic Affairs

The particle-like size can be obtained by a known action of this technique. &lt; Wanfa, for example, the pharmaceutical composition or formulation is preferably in a unit dose. In the middle, the preparation is subdivided into a packaged preparation containing an appropriate amount of living unit dosage form. The packaging = early BIT DOSE. Agents, such as tablets and capsules in small packages, are powdered in a precise amount. And the unit dose can be a capsule, a tablet, a capsule thief :! As such, or it may be an appropriate amount of any of these packaged formulations. The formula R p * dagger in the preparation of these dosage forms is yet another. Use 士 为 顾 而易 # · 彳 u, or publish to the artist who is accustomed to the art, Easton, Pennsylvania, 16th edition, coffee. ) f Example This step is illustrated by the following illustrative examples. Unless otherwise indicated, percentages are by weight. Unless otherwise specified, temperatures are indicated in degrees. Unless otherwise specified, all reagents were purchased from Aldrich's subsidiary, Milwaukee, Wisconsin. The following preparations and examples are intended to illustrate the invention, but not to limit its scope. Example 1 Preparation of compound nasal dihydrodiamiline_2_ylmethylamino group) Preparation of benzylmethylsulfonium MamineΗ Ν H -HCI By powdering please read-read the back-fist item. F irI 装Page order Hydrogenated N- [3_ (4,5 · dihydro-1H_imidazole_2 · ylmethoxy) phenyl] methanine-83 517049 A7 B7 V. Description of the invention (81) Amine

H2NnV ^ V ^ 〇H DMF I || + NaH + BrCH2CN ^ | Sodium hydride (3.5 g, 60%) stored in mineral oil was washed with hexane to remove the oil, and then suspended in 40 ml of N, N-dimethylformamide (DMF). The mixture was cooled in an ice bath, and then treated dropwise with a solution of 8.0 g of 3-aminophenol in 40 ml of N, N · dimethylformamide. After the addition of 3.aminophenol, the ice bath was removed and the reaction mixture was stirred at room temperature for 14 hours. The mixture was cooled again in an ice bath and treated with 9.2 g of bromoacetonitrile. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into ether, washed with water, dried, and evaporated to give 5 · 8 g of (3-aminophenoxy) acetonitrile as a dark oil. Η (Please read the notes on the back before filling this page)

Η2Ν ^^ / 〇,

.CN + CH3S02C1 Printed by the Consumers' Cooperative of I Standards Bureau, Ministry of Economic Affairs, (3-aminophenoxy) acetonitrile (3.0 g) was dissolved in 12 ml of pyridine, cooled in an ice bath, and cooled at 3.47 Treat with g of methanesulfonium chloride and stir at room temperature for 3 hours. The mixture was poured into ethyl acetate, washed with hydrochloric acid and then with water, dried, and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate: hexane (3: 7) to obtain 3.0 g of N- (3-cyanomethoxyphenyl) -sulfenamidamine. An equivalent amount of this product was crystallized from ethyl acetate: hexane (3: 7) to obtain a solid, mp 91-92 ° C. 84- The size of this paper applies to Chinese National Standard (CNS) A4 (210X 297 mm) 517049 A7 B7 V. Description of the invention (82 Η

CH3S02NL ^ n.0v ^ CN

Η ΝΗHCI HC1 ^ CH3S02L ^^ / 〇 CHCl3 l ^ J

N- (3-cyanomethoxyphenyl) -methanesulfonamide (1.0 g) was dissolved in a mixture containing 20 ml of chloroform and 0.25 ml of absolute ethanol (EtOH). The reaction mixture was cooled in an ice bath and saturated with hydrogen chloride gas. The mixture was allowed to slowly warm to room temperature and stirred for 16 hours. The solvent was evaporated and 1.1 g of 2- (3.methanesulfonamidoaminophenoxy) -ethylammonium iodide remained. ΝΗ-υη 乙 乙, 卩 XT

WH · HCI Diamine

MeOH CH3S〇2N, ^^ 〇

H-HCI (Please read the notes on the back before filling out this page) Printed by the Consumer Standards Cooperative Office of the Central Bureau of Standards of the Ministry of Environmental Protection 2-(3 -A Continued S &amp; Aminoamine-based Emulsion)- Ethyl acetate (1.0 g) was suspended in 12 ml of absolute methanol (MeOH) and treated with 0.16 g of ethylenediamine. After 8 hours at room temperature, the solvent was evaporated. The residue was purified by silica gel chromatography eluting with methanol: dichloromethane ·· ammonium hydroxide (16: 84: 0.1). By adding 1.0M hydrogen chloride in diethyl ether, it was converted into a hydrogen chloride salt to obtain 0.16 g of N- [3- (4,5-dihydro-1H-imidazol-2-ylmethoxy) phenyl hydrochloride. ] Methanesulfonamide, melting point 183-187 ° C. Example 1A Hydrogenated N- 丨 3- (4,5-dihydro-1H-imidazol-2-ylmethoxy) phenyl 1methanesulfonium 1. Preparation of amine monohydrate (3-aminophenoxy ) Acetonitrile Preparation

Ts〇

, CN

KOtBu, DMF / THF -85- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm)

.CN 517049 Employees' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China F A7 B7 V. Description of the invention (83) Dissolved in 40-mL tetrahydrofuran / 12-mL Ν, Ν- In a solution of dimethylformamide, 3-aminophenol (100 g) was dissolved in a solution of 16 ml of tetrahydrofuran / 4 ml of Ν, Ν-dimethylformamide, so that the reaction temperature did not exceed 25 Add at a rate of ° C. After 30 minutes, a solution of methyl cyanate (17.5 g) in 12 ml of tetrahydrofuran / 4 ml of N, N-dimethylformamide was slowly added to the phenoxide solution to maintain the temperature at Or below 25 ° C. The resulting slurry was stirred for 3 hours, at which time TLC analysis indicated that the reaction was complete. The crude mixture was partitioned between toluene (200 ml) and water (200 ml), and the aqueous phase was extracted with 100 ml portions of toluene. The combined organics were washed with IN NaOH and water, and then concentrated to an oil (16.0 g). The crude product was typically taken directly to the next step without purification. 2; _cyanomethoxyphenyl) -methanamine preparation

In a solution of crude (3-aminophenoxy) acetonitrile (about 12 "grams) in toluene (50 ml), pyridine (6.6 ml) and methanesulfonyl chloride (6.3 ml) were dissolved at 50 ° C. Add and warm the resulting mixture to the surrounding temperature. After 2 hours, the crude product mixture was partitioned between 1N hydrogen acid (100 mL) and ethyl acetate (100 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organics are washed with water, and then concentrated by coexistence displacement with isopropanol. The resulting mixture was cooled to 5. 〇 After that, the white crystalline product was collected, washed with ice isopropyl alcohol and dried to obtain 12.14 -86- This paper size applies the Chinese National Standard (CNS) A4 specification (21〇 &gt; &lt; 297 mm) ---- ---- ^ 装-(Please read the notes on the back before filling this page)

1T d 517049 A7 B7 V. Description of the invention (84) g (65.1% yield, based on cyanomethylsulfonate sulfonate) N- (3-cyanomethoxyphenyl) -sulfonamide (as HPLC showed 99.8% purity). If necessary, this material can be recrystallized from isopropanol. 3. Hydrochlorination> 1- [3- (4,5-dihydro-111-imidazol-2-ylmethoxy) phenyl 1 methanesulfonamide monohydrate preparation ΝΗ · ΗΟΙ

Printed by the Consumers Cooperative of the Central Bureau of Standards of Didi (please read the precautions on the back before filling this page). Pass in gaseous hydrogen chloride, N- (3-cyanomethyloxyphenyl) -methanesulfonamide (10.0 g ) Store in a mixture containing chloroform (60 ml) and ethanol (3.0 ml) for 8 minutes (to reach saturation), keeping the temperature below 15 ° C. The resulting mixture was stirred at the surrounding temperature for 3 hours, during which the intermediate phosphonium imine hydrochloride precipitated from the transparent uniform solution. The excess of hydrogen chloride was discharged from the reaction vessel by nitrogen, and the resulting slurry was completely dissolved by adding methanol (60 ml). This solution was then added to a solution of ethylenediamine (2.85 ml, 2.56 g) in methanol (20 ml) over a period of 15 minutes, maintaining the temperature at or below 25 ° C. After 1 hour, the solvent was replaced by a steaming crane with a 9: 1 mixture (100 ml) containing isopropanol and water. After the mixture was concentrated to about 90 ml, the resulting slurry was cooled and the crystalline product was collected. After washing with isopropanol, the solid was dried to obtain 11.97 g of hydrochloride N- -87-. This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210X297 mm). 517049 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Cooperatives Indo A7 B7 V. Description of the invention (85) [3- (4,5-dihydro · 1H_imidazol-2-ylmethoxy) phenyl] methanesulfonamide monohydrate (yield 86.8%, (The purity was 99.8% by HPLC). If necessary, recrystallize this material from 9: 1 isopropanol / water.

Example 1B 1 ~ ^ 1 ^^ _ "3- (4.5-Dihydrazine-111-imidazol-2-ylmethoxy) Benzoum 1 醯 M_ (R = Et), new, propyl chloride-benzoic acid ^ 3- (45-Diargon-1H-Mijun-2-a certain methyl-yl) phenyl 1-amine (R = n_pr), and hydrochloride N · 丨 3- (4,5_dihydro- Preparation of 111-fluorenyloxybenzene 1 jasmonamidine (R = CaHs) Η

H · HCI R1 = Et-, η-Pr-, in a manner similar to that described in Example 1, except that ethanesulfonyl chloride was used instead of sulfonyl chloride to prepare hydrochloroethanesulfonic acid [3- ( 4,5-dihydro-lΗ-imidazol-2-ylmethoxy) phenyl] g amine (R = Et), melting point 155.7-157.7. (:.) Hydrogenated propane-1-sulfonic acid [3- (4,5-dihydro-1H] was prepared in a similar manner to that described in Example 1, except that propanesulfonyl chloride was used in place of methanesulfonyl chloride. -Imidino-2-ylmethoxy) phenyl] fluorenamine (R = n_Pr), melting point 129 · 3-132 · 9 ° C 〇 In a manner similar to that described in Example 1, except that benzenesulfonium Chlorine replaced methanesulfonium chloride to prepare hydrogenated N- [3- (4,5-dihydro-1fluorene-imidazol-2-ylmethoxy) -phenyl] benzenesulfonamide (R = C6H5), Melting point is 241.5-243.5 ° C. Example 2 Hydrochlorinated N- "5- (4,5-dihydro-1H-imidazol-2-ylmethoxy V2-methyl-88 This paper is applicable to Chinese national standards ( CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page), τ __ 丨 517049 A7 V. Description of the invention (86 CH3S02 based on 1 methylamine amine f ^ N-

HCI ΐ = [5,, 5-diaza-2.ylmethoxyamethyl · phenyl]

+ BrCH2CN K2CO3

Methyl ketone dissolve 'methyl quinol (5.0 g) (TCI USA, Putran, OR) with 470 g bromoacetonitrile in 30 ml 2-butanone; then 13.5 g Potassium was added, and the mixture was stirred and heated at 70 ° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into ethyl acetate, washed with water, dried, and evaporated 'to obtain 6.1 g of (4 • methyl_3_nitrophenoxy) acetonitrile as a brown oil.

1) SnCl2 2H20

Printed by a member of the Central Standards Bureau, Consumer Cooperative 2) EtOAc (4-methyl-3-nitrophenoxy) acetonitrile (60 g) was dissolved in 120 ml of ethyl acetate, and 21.8 g Tin (II) chloride dihydrate treatment; the mixture was stirred at 70 ° C. for 2 hours. The mixture was cooled, poured into a saturated solution of sodium bicarbonate, extracted with ethyl acetate, dried, and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate: hexane (7: 3) to obtain 2.7 g of (3-amino-4-methylphenoxy) acetonitrile. -89- This paper size is applicable to China National Standard (CNS) 8-4 specification (21〇 &gt; &lt; 297mm) (Read the precautions on the back before filling in this page)

517049 A7 B7 V. Description of the invention (87

Eridine CH3S02C1 CH3S02-^

XN Dissolve (3-amino-4-methylphenoxy) acetonitrile (2.6 g) in 10 ml of pyridine and cool in an ice bath; add 2.29 g of methanesulfonyl chloride; and place the reaction mixture in 5 Stir at ° C for 1 hour. The mixture was poured into ethyl acetate, washed with hydrogen acid, then extracted with water, dried, and evaporated to obtain 3.5 g of N- (5-cyanomethoxy-2-methylphenyl) -methanesulfonamide. . ch3s〇2

EtOH HC1 CH2C12

〇C2H5

NH -HCI (Please read the notes on the back before filling this page) Dissolve N- (5-cyanomethoxy-2-methylphenyl) -methanesulfonamide (3.48 g) in 70 ml chloroform And 3.5 ml of ethanol. The reaction mixture was cooled in an ice bath and saturated with hydrogen chloride gas (Matheson, Newark, CA), allowed to slowly rise to room temperature, and held for 16 hours. The solvent was evaporated and 5.2 g of 2- (4-fluorenyl-3-methanesulfonylaminophenoxy) -ethylacetimidate hydrochloride remained.

• HCI CH3S02

Ethylenediamine ch3S〇2 NH. Um a-ϊ N- Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Li ^

Ethyl 2- (4-methyl-3-methanesulfonamidophenoxy) -acetamidate hydrochloride (5.2 g) was dissolved in 50 ml of methanol in MeOH. To this mixture, 1.05 g of ethylenediamine was added, and the mixture was stirred at room temperature for 6 hours. Solvent-90- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 A7 B7 V. Description of the invention 88 The residue is evaporated by ethyl acetate: methanol: isopropylamine (92: 5: 3) Purified by silica gel chromatography as a dissolution solvent to obtain 3.3 g of product. The hydrogen chloride salt was prepared by adding 1M hydrogen chloride in diethyl ether, and the product was crystallized from methanol: ether (1: 3) to obtain 3.3 g of N- [5- (4,5-dihydroimidazole · 2) hydrochloride. -Methylmethoxy) -2-fluorenyl] methanesulfonamide, melting point 21TC. Example 2A Hui JU N-Γ5- (4,5-dihydro-1H-imidazol-2-ylmethyl gas P-2- 氲 1 amine (R = C1) and hydrogenation N- "5- ( Preparation of 4,5_difluorene-1Η-imidazole and its methoxyl) -2-fluoro · phenyl 1 methylamine (R = F) Η

H * -HCI --------- · install-(Please read the notes on the back before filling this page) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards R7 = Cl-, F · Similar The method described in Example 2 except that 4-methyl-3-nitrophenol was replaced by 4-_3_nitro group as the starting material, and hydrochloride ν · [5 ^ 4, 5_ monooxy-1Η_amijun-2-ylmethoxy) -2-qi-phenyl] pyrene amine ci), melting point 228.2-228.5 ° C. A method similar to that described in Example 2 except that 4-fluoro-3-nitrobenzine was used as the starting material (based on the method described by Meurs et al., Tetrahe Hrnn, (1991) 11: 705 Prepared by the general method described) instead of renmethyl-3_nitrophosphonium, and hydrogenated N- [5- (4,5-dihydro] H_imidazol-2-ylmethoxy) -2 -Fluoro · phenyl] methanesulfonamide (R = F), melting point 2117-212 4. 〇. Example 20_Jlfl N- [3- (4,5 -dihydro-1H-Weijun ·; 2_methylmethoxyfluorene) -2-a certain stupid -91-This paper size applies Chinese national standards (CNS) A4 specification (210 × 297 mm), 11 J ·. Preparation of 1 methylamine_amine CH, Ν-

517049 A7 B7 V. Description of the invention (δ9

• HCI was prepared by a method similar to that described in Example 2 except that 2-methyl-3-nitrophenol was used as a starting material instead of 4-methyl-3-nitrophenol to prepare N-hydrochloride. [3- (4,5-dihydro · 1Η · imidazol-2-ylfluorenyloxy) · 2-gas-phenyl] methanesulfonamide, melting point 236.7-237.3 ° C.

Example 2C Air-gasification 1 ^-"6-chloro-3_ (4,5-dirat-1! 11-weikou-2-ylmethoxy) -2-methyl (Please read the precautions on the back first (Fill in this page)

N_ [6-Gas-3- (4,5-dihydro-1H-imidazol-2-ylmethoxy) -2-methyl-phenyl] methanesulfonamide employee consumption Printed by a cooperative

O ^ RT (ΟΝ), α〆 92- The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 517049 A7 B7 V. Description of the invention ^

H ^ CSOpNI

• HC1 1. AlM ^ ^ NC ^ CH ^ NHj

2. HCl ^ O (Read the precautions on the back before filling this page) k 2,4-Dinitro-3-methylamine

1T 2, cardiodinitro-3-methylamine benzene was prepared by a modification procedure described by Meisenheimer et al. £ lie · Ber · (19〇 ^ 1 ··· 2533). Stir 2,6-dinitrotoluene (55.0 g) and tritium hydroxide (55.0 g) in 4 liters of ethanol until a solution is produced. Add 2N potassium hydroxide solution (55.0 ml) in one portion. The resulting mixture was allowed to stir for 24 hours. A gasification solution (71 g) dissolved in water (350 ml) was added, and the mixture was stirred for another hour. The reaction mixture was evaporated under reduced pressure. The residue was placed under reduced pressure. Partition between ethyl acetate (750 ml) and 50% saturated sodium gas solution (500 ml). The ethyl acetate extract was separated and dried over magnesium sulfate. After the crude product (52.6 g) was obtained, it was applied to silica gel, and the reaction was carried out by first eluting with ethyl acetate: hexane (1: 3) and then ethyl acetate: hexane (1: 2). Chromatography, to obtain 36.0 grams of product, melting point i26.7_131.4 ° C. 3-Gas-2.6-Dinitromethylbenzyl through the Ministry of Central Standards Bureau staff consumption She Yin t Place copper (II) chloride (29 · 5 g) and dry acetonitrile (350 ml) in a three-necked 1 liter flask equipped with an overhead stirrer, a condenser tube, and a nitrogen inlet tube, and heat to 60-65 Ό. Add the third butyl nitrite (32 6 ml) in one portion, and then add 2,4-dinitro-3-methylaminebenzene (36.0 g) to the above mixture in portions. Allow the mixture to the temperature Stir for another 15 minutes. The reaction mixture was cooled to 罜 and evaporated under reduced pressure. The residue was partitioned between ether (650 ml) and 6N hydrochloric acid solution (650 ml). The ether solution was 93 517049 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ΑΊ B7 V. Description of the invention (⑺) Separate, extract and wash with saturated sodium gas solution (500 liters), and then dry over magnesium sulfate to obtain the crude product. The silica gel was subjected to flash chromatography with diethyl ether to obtain 37.8 g of a yellow solid. 3.4-Gas-2-methyl-3-nitroaminebenzene Gas-2,6 &gt; Dinitrotoluene (18.0 g), cyclohexene (^ 1 ml), and 10% palladium on carbon (4.5 g) The mixture stored in ethanol (350 ml) was heated under reflux under a nitrogen atmosphere for 1.5 hours. The reaction mixture was cooled to room temperature, filtered through celite, and then evaporated under reduced pressure. The residue was evaporated. Dissolve in ether and filter through a short silica column. Evaporate the ether to obtain 148 g of orange solid. Preparation of 3- 4 -chloro-2-methyl-3 -nitrobenzene will contain 4-gas-2- A suspension of methyl · 3 · nitroamine benzene (20.9 g), water (200 ml) and fluoboric acid (纟 6 亳 L) was heated to a stagnation until almost completely dissolved, and then cooled to 0-5 ° C . A solution of sodium nitrite (8.11 g> in water (20 ml) was added dropwise to the above mixture, and the mixture was stirred in ice for another 30 minutes. The precipitated diazonium salt was filtered off, and Wash with a small amount of ice water. Add the wet diazonium salt to a hot (100-12. (:) solution containing water (230 ml), concentrated sulfuric acid (115 ml) and sodium sulfate (35 g) at a time, and make it Stir for 4 hours. The reaction mixture is cooled to room temperature and extracted with diethyl ether (700-liters in two portions). The combined diethyl ether extracts are washed with a saturated sodium gas solution (500 ml), and then It was dried over magnesium sulfate. After evaporation, a crude product (17.5 g) was obtained. It was purified by flash chromatography on a lithotripsy gel and eluting with two gas methane to obtain 7.6 g of a yellow solid. The 2-methyl-3 _ confirmation basis is as follows, similar to Jing Su -94- This paper size applies Chinese National Standard (CNS) A4 specification (21 οχ 297 mm) (Please read the note on the back first (Fill in this page again)

T 517049 A7 B7 V. Description of the invention C * is prepared by the method of NCS chlorination in the method of Oberhauser, _J. Org (1997) Z: 4504-4506. CH3

CH3CN, 75c

NCS, CF3SO3H

Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the People ’s Republic of China (50.0 g) was combined in dry acetonitrile (500 ml), and it was heated at 75 ° C under nitrogen atmosphere for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether (650 ml), and water, 100 /. Sodium bisulfate solution, water and finally washed with saturated vaporized sodium solution. The solvent was evaporated to obtain a crude product, which was 'extracted on Scopolite', and subjected to step chromatography with acetone: hexane (1.9) to obtain 16.8 g of a yellow solid. 1: plastic of __ (4-chloro · 2-methyl-3_nitrobenzyloxy) acetonitrile: 4-chloro · 2 · methyl-3-nitrophenol (7.6 g), bromoacetonitrile (3.4 ml ), And a mixture of potassium carbonate (16.8 g) in 2-butanone (80 ml) was heated at 800 ° C for 2 hours under a turbulent atmosphere. The reaction mixture was cooled to room temperature and then filtered to remove salts. The filtrate was diluted with diethyl ether (200 ml), extracted with a saturated sodium gas solution, and then dried over magnesium sulfate. The solvent was evaporated to give a yellow solid (9.1 g). ^ —— Preparation of Amino-4-Gas-2-methylphenoxy) acetonitrile will contain (4-chloro-2-methyl-3-nitrophenoxy) acetonitrile (9.1 g) and zinc (fine Powder) (10.5g) stored in glacial acetic acid (90ml) at 60 · 65ι at nitrogen-95- This paper size applies the Zhongguanjia Standard (CNS) A4 size (21Qx297 male sauce) ---- ^ ----- 0 ^-(Please read the notes on the back before filling out this page), 1T 1 · 517049 Α7 Β7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (93 ) Heat in the atmosphere for 4 hours. The reaction mixture was cooled to room temperature and then filtered through celite. The filtrate was evaporated under reduced pressure, and the residue was partitioned between ether (500 liters) and 10% ammonium hydroxide solution (<500 liters). The ether solution was separated, washed with a saturated sodium vaporized solution, and dried over osmium sulfate. The solvent was removed under reduced pressure, and the residue was placed on a silica gel and subjected to flash chromatography using ethyl acetate: hexane (1: 4) to obtain 4.76 g of a pale yellow oil, which Crystallized on standing. Ί ———— Chloro-3-cyanomethoxy-2-methyl-benzyl) Methanesulfonamide in nitrogen atmosphere 'will (3-amino-4 -chloro_2_tolyloxy) Acetonitrile (4.76 g) was dissolved in pyridine (45 ml) and cooled in an ice bath. Add methylated tritium gas (2.06 liters) dropwise, and stir the leakage mixture at room temperature overnight. The reaction mixture was evaporated under reduced pressure to obtain a residue, which was applied on a crushed stone gel and firstly ethyl acetate: hexane (1: 2), then ethyl acetate: hexane (1: 1) The elution was performed by flash chromatography to obtain 5.36 g of a mixture of mono- and di-methylated products of 80:20 respectively. This mixture was used in the next step without further purification. 8: _ Qi-3 · (4,5 · Dihydrazine-1Η-imidazole_2_ylmethylsulfanylmethyl_phenyl] Methanesulfonamide will prepare ethylenediamine (5.21g) and Toluene (40 liters) was placed in a three-necked 2000 ml three-necked flask equipped with a stir bar, a nitrogen inlet tube, a baffle, and an addition funnel. The mixture was cooled in an ice bath, and 2.0, A solution of trimethylaluminum (39 ml) in toluene was added dropwise, and then it was stirred at room temperature for 2 hours. N- (6-chloro-3-cyanomethoxy-2-methylbenzene) Base) Methanesulfonamide (5.36 -96-) This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page): Binding · Order d 517049 A7 B7 • HC1 V. Description of the invention (94 g) is added in one part. Then the mixture is heated under reflux for 6 hours and allowed to stir overnight at room temperature. Carefully add methanol, then heat under reflux for 30 minutes, and Cool to room temperature. Filter the reaction mixture through celite and evaporate the filtrate to dryness. Place the residue on a silica gel and start with ethyl acetate: formaldehyde · 2-propylamine (40: 5: 1), then ethyl acetate: methanol · 2-propylamine (40: 10: 2) was lysed and flash chromatography was performed, and 4.74 g of a solid was obtained after evaporation. The solid (free state base) was suspended in methanol (50 ml), and HCl in ιμμ stored in ether (30 ml) was quickly added and allowed to stir at room temperature for one hour. The product was filtered off, It was washed with a small amount of ether and dried to give 4 83 g, melting point 268.0-269.1 Torr.

Example 2D Imperial Chloride N_ 『6 · Bromo-3 · (4 · 5_Dihydro-1H-imidazole_2 · Methylmethylamino group · methyl · phenyl 1 Methanesulfonamide floc preparation ch3 is similar The above-mentioned method for preparing N- [6-qi-3- (4,5-dihydro-iH_imijun_2_ylmethyllactyl) · 2-methyl-phenyl] methylidene_amine, Using copper bromide (M) instead of gasified copper (II) to prepare N- [6 · bromo-3- (4,5-dihydro-1Η- 味 峻 _2-ylmethoxy) -2 · Methylphenyl] methanesulfonamide, melting point 27ΐ 5_2719χ :.

Example 2E Chlorochloride 1 ^-"5-chloro-3- (4,5-dihydro-11 ~ 1-mi rabbit &gt; 2-ylmethyl ^ -methyl-97) This paper size is applicable to Chinese national standards (CNS ) A4 size (210X297mm) II Approved clothing I Order I (Please read the precautions on the back before filling out this page) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Printing 517049 A7 B7

V. Description of the invention (S3 phenyl 1 mesylate ch3 H3CS〇2Nhk ^^ J ^^ / 〇

• HC1

Cl was used similarly to the above to prepare N- [4-Ga-3- (4,5-dihydro_1 氢 -midot-2 · ylmethoxy) -2-methyl-phenyl] methylamine Method, except that the starting material is 5-chloro · 2-fluorenyl-3-nitroaniline (Example 60) described in Scheme Q, and N- [5-chloro · 3- (4 , 5-Dihydro-1H-imidazol-2-ylmethoxymethylphenyl] methanesulfonamide, melting point 198.1-199.3 ° C. Example 2F chlorinated! ^ [-丨 6_ 鼠 -3- (4,5-Diazepine-11 ~ 1-taste salyl_2_ylmethoxy) Alternative to 2-methyl-phenyl 1-methanesulfonamide? H3 MsHN

(Please read the precautions on the back before filling out this page) 装 Binding and printing printed by hydrogenation N- [6- 气 -3- (4,5-dihydro-1H-imidazole) 2-ylmethoxy) -2-methyl-phenyl] methanesulfonamide

H 5% Pd / C H2

H2 / EtOH

, 〇H BrCH2CN H2-Cs2C〇3 / MEK CH3

-98-This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21 OX 297 mm) 517049 A7 B7 V. Strict description of invention

MsCI

Pyr / CH2C! 2

CK ^ MsHN

° ν ^ Ν Method A 1. HCI (g), EtOH, CH2CI2 2. H2NCH2CH2NH2, MeOH Method B H2NCH2CH2NH2 / AIMe3 toluene .CN tBuOCI, tBuOH, CCk MsHN 0 ° C to room temperature> c

1. Preparation of 2-methyl-3-aminophenol

5% Pd / C, H2, EtOH

(Please read the precautions on the back before filling out this page.) Printed in a 1 liter Parr hydrogenation flask by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Standards, and put 2 · methyl-3-nitrophenol (25 g, 0.163 mol) ) Dissolved in 170 ml absolute ethanol. The flask was purged with nitrogen. Palladium on carbon (1.73 g, 1.6 mmol) was added and the mixture was hydrogenated (40 psi H2) in a Parr apparatus for 1.5 hours. The flask was vented and flushed with nitrogen. The catalyst was removed by filtration through a Watman GF / F filter paper. After removing ethanol under reduced pressure, 20.1 g (100% yield) of 2-fluorenyl-3-aminophenol was obtained as a light brown solid. ^ 2. Preparation of (2-methyl-3_aminophenoxy) acetonitrile

BrCH2CN, CS2CO3 MEK, r.t.

Dissolve 2-methyl-3-aminophenol (20.1 g, 0.1 63 moles) in methyl ethyl ketone (MEK) (150 ml). Distilled carbonic acid (106 g, 0.326 mmol) -99- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 Α7 B7 5. Description of the invention (97 after adding 'the bromoacetonitrile ( 29.3 g, 0.245 mmol) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 14 hours and then filtered through a coarse-grained funnel. The solid was washed with ethyl acetate (2 X 100 ml). , And the combined washing solution and filtrate were concentrated under reduced pressure to obtain 20.8 g (yield 79%) of (2-fluorenyl-3-aminophenoxy) acetonitrile, which did not require further purification. ^ ~ K3-cyanofluorenyloxy-2-methylphenyl) methanesulfonamide

H2N &quot; X ^ 〇x / CN

MsCI, pyr, CH2CI2

MsHN

A method similar to that described in Example 1 was used to prepare N- (3-cyanomethyloxyphenyl) methanesulfonamide from (3-aminophenoxy) acetonitrile to prepare (3-cyanomethoxy 2-methylphenyl) methanesulfonamide. · ———— K6 · Chloro-3-cyanomethoxy-2-methylphenyl) formamidine

MsHN

tBuOCI, tBuOH, CCl ^

MsH

(Please read the precautions on the back before filling out this page) Printed by the Consumers Cooperative of the Central Bureau of Standards of Didi t 0 ° C to rt will be N- (3-cyanomethoxy_2_methylphenyl) methanesulfonate Amidine (187 g, 778 moore) was suspended in a 1: i mixture (80 ml) containing tertiary butanol and carbon tetrachloride and cooled in an ice bath. Tertiary butyl hypochlorite (TCI, 0.85 g '7.78 mmol) was added dropwise. The mixture was maintained at 々1 overnight and then warmed to room temperature. The volatiles were removed under reduced pressure. N- (6-gas-3-cyanomethoxy-2 · methylphenyl) methanesulfonamide (105 g, yield 49%) was obtained by recrystallization from toluene. ^ 100- Dimensions are not applicable to China National Standard (CNS) A4 (210X297 mm) 517049 Α7 Β7 V. Description of the invention (98) 5. Hydrochlorination, ^ 『6-chloro-3- (4,5- Dihydro-1 simiazol-2-ylmethoxy) _ Preparation of 2-methyl-phenyl 1 sulfonamide (Please read the precautions on the back before filling this page)

MsHN

ON 1. HCI (g), EtOH, CH2Cl2

2. Hydrogen chloride N- [3- (4,5-dihydro · 1 类似 -imidazole-2-) prepared from (3-aminophenoxy) acetonitrile in a similar manner as described in Example 1 using H2NCH2CH2NH2, MeOH. Methyl methoxy) -2-methyl-phenyl] methanesulfonamide, prepared from N- (6-chloro-3-cyanomethyl-2-methylphenyl) methanesulfonamide N- [6-chloro-3- (4,5-dihydro-1 smidazol-2-ylfluorenyloxy) -2-methyl-phenyl] methanesulfonamide hydrochloride.

Example 2 Preparation of N- (3-, 4-dihydro-1H.imidazol-2-ylmethoxy V2,6-dimethylphenyl 1 sulfonamide) H ^ CSOpNKs. ^^ J ^. N- [3- (4,5-Dihydro-1Η · imidazol-2-ylmethoxy) _2,6 · dimethylphenyl] Methanesulfonamide was printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Li

-101-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517049 A7 _ B7 V. Description of the Invention (99) JL 2,4 · Dinitro- Preparation of m-dimethylbenzyl 2,4-dinitro-m-xylene is prepared according to the method described in US Pat. No. 4,564,640. Preparation of U, 4-dimethyl-3-nitroaniline containing 2,6-dinitro, m-xylene (ιι · 2 g), and 10% palladium on carbon (6? Q 亳 g) in three In ethylamine (36 liters), heat to reflux under a nitrogen atmosphere. Formic acid (9.25 ml) was added dropwise to the above mixture with vigorous stirring. After the addition, the mixture was stirred under reflux for another 15 minutes and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through celite. The filtrate was extracted with brine and dried over magnesium sulfate. After evaporation, 9.51 g of a yellow solid was obtained. 1 Preparation of 2,4-dimethyl-3-nitrophenol Put 2,4-dimethyl-3-nitroamine benzene (9.5 g) in concentrated sulfuric acid (15.5 ml) and water (57 ml) ) Solution is heated to complete dissolution, and then cooled to room temperature. Water (143 ml) was added and the mixture was cooled to 0-5X :. A solution of sodium nitrate (4.03 g) in water (8 ml) was added dropwise to the above mixture, and the mixture was stirred in ice for another 15 minutes. Add the above diazonium solution dropwise (via an ice-covered addition funnel) to a hot (1050 10 ° C) solution containing concentrated sulfuric acid (60 liters) and water (91 ml); adjust the addition rate to the temperature Keep at 105-110 ° C. After the addition, the mixture was heated for another 15 minutes. The reaction mixture was cooled to room temperature and then extracted with three portions of ethyl acetate (250 ml). The combined extracts were washed with brine and then dried over magnesium sulfate. After evaporation (17.5 g). Place the crude material on silica gel and perform a rapid layer with two gas methane dissolution. -102- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling This page) Order d 517049 Α7 _____ Β7 V. Description of the invention (10 °) Analyze the technique to obtain 5.15 g of orange solid. ^ _ And-[3- (4,5-dihydro-1Η-imidazole-2-a methoxy) -2.6_ dimethyl a cuminyl 1-methanesulfonamide floc similar to the above to prepare N- [6 · Chloro-3- (4,5-dihydro-1Η-imidazol-2-ylmethoxy) -2-methylphenyl] methanesulfonamide, but the starting material is obtained from 2 above , 4-Dimethyl-3-nitrophenol, and N- [3- (4,5-dihydro-1H-imido-2-ylmethoxy) · 2,6-dimethylbenzene was prepared Methyl] methanesulfonamide, melting point 216.3-216.8 ° C. Example 2 Η ΑΝΝ- 『5- (4,5_dihydro-1Η-imidazolemethoxy) _2,4-dimethylbenzene N- [5- (4,5-mono-iron i-lH-taste mouth_2-ylmethoxy) · 9 4_dimethylphenyl] methanesulfonium Amine (Please read the notes on the back before filling out this page) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards

-103- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 517049 A7 .__ B7 ______ V. Description of the invention (1101) ^ —— Dimethylbenzyl) The preparation of acetamidine 2,4-Dimethylaminebenzene (10.0 g) and cluster anhydride (9.26 ml) were combined all at once, and stirred at room temperature for 2 hours. The resulting solid material was dissolved in ethyl acetate (300 liters), washed with a 0.5 M sodium hydroxide solution, brine, and dried over magnesium sulfate. After evaporation, 105 grams of a white solid were obtained. 2 .... Preparation of N- (2,4-dimethylnitrophenyl) acetamidine A mixture containing concentrated nitric acid (20 ml) and concentrated sulfuric acid (20 ml) was cooled in an ice-salt bath To 0 ° (^.) ^-(2,4-dimethylphenyl) acetamide (9.5 g) was added in portions at a temperature lower than 5 ° C. The mixture was then frozen in ice. Stir for another 1 hour. Pour the reaction mixture into ice (500 grams) with stirring and extract with ethyl acetate (1 liter). Ethyl acetate extract is washed with brine and dried over magnesium acetate After evaporation, a crude material was obtained, which was applied to silica gel and subjected to flash chromatography with ethyl acetate: hexane (1: 1) to obtain 9 64 g of a pale yellow solid. K 2 , 4-dimethyl_5_nitroaniline printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs c Please read the notes on the back before filling this page} d will contain Ν- (2,4-dimethyl A mixture of methyl-5-nitrophenyl) ethylamine, water (24 ml), concentrated sulfuric acid (12 ml) and ethanol (120 ml) was heated under reflux in a nitrogen atmosphere for 4 hours. The ethanol was reduced under reduced pressure. evaporation, The residue was partitioned between ethyl acetate (250 ml) and brine (150 ml). The salt solution was re-extracted with ethyl acetate. The combined acid ethyl acetate extract was then dried over magnesium sulfate. After evaporation, a crude product was obtained, which was subjected to flash chromatography on a stone-cut gel, and subjected to flash chromatography with ethyl acetate · hexane (1: 4) to obtain 4.63 g of a pale yellow solid. The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 A7 ------ B7 V. Description of the invention (102) ^ ~ 乳. 瓜 Nf 5- (4,5 -Diazo-1H- Weijun-2 -ylmethyl) 2 4 Di-J-ylphenyl 1 methyl amine is widely prepared similar to the above for the preparation of N- [6-qi_3 · (4,5_dihydroimidazole_2_yl (Methoxy) -2-methylphenyl] methanesulfonamide, but the starting material is 2,4-dimethyl-5-nitroaniline from above, and hydrochloride is prepared. N_ [5_ (4 5_ Dihydro-i H-imid-2-ylmethoxy) _2,4-dimethylphenyl] methanesulfonamide, melting point 219.7-219.9 ° C. Example 21 Hydroxide N,! ^ _ Monomethyl_N '· 丨 3- (4,5-dihydro-1H-imidylmethylamino) -2,6_dimethyl one phenyl 1 methanesulfonate Amine amine prepared CH3 • HC1 A method similar to the above for the preparation of N- [3_ (4,5-dihydro-1H-imidazol-2-ylmethoxy) -2-methylphenyl] methanamine However, the starting material is obtained from the above 3-amino-2,4-dimethylphenoxy) acetonitrile and N, N-dimethylamine sulfonium gas to prepare hydrogenated N, N- Dimethyl-N, · [3- (4,5-dihydro-1H-imidazol-2-ylmethoxy) _2,6_difluorenylphenyl] methylene diamine, oak point 227.7-228.1 ° C.

Example 2J or N-5-(4,5 -dihydro-1Η-Weitu · 2 -methyl methyl gas)-2-Preparation of via phenyl-phenyl 1 sulfonamide Paper size applies to China National Standard (CNS) Α4 specification (210 × 297 mm) ---------_ batch clothing ------ 1T ------ 0 (Please read the precautions on the back first Refill this page) Ο

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517049 A7 B7 V. Description of Invention (103

N- [5- (4,5-dihydro-1H-imidazole · 2 · methylmethoxy) -2-hydroxy [phenyl] methanesulfonamide

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs for $ 1! _ · (4_Hydroxyphenoxy) acetonitrile The suspension in 50 liters of N, N-dimethylformamide was cooled in an ice bath, and 10 g of hydroquinone was added to dissolve 50 ml of N, N-dimethylmethanamine. In the liquid. After the gas cannon stopped, the reaction mixture was stirred at 70 ° C. for 3 hours and then placed in an ice bath again. 2 · 0 g of bromoacetonitrile was added gradually. After the addition ', the ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into ethyl acetate, and ice water was added. The mixture was acidified with concentrated hydrochloric acid, washed with brine, dried (MgS04), and evaporated to dryness. The residue was purified by celite gel chromatography using ethyl acetate / methane gas (3:97) as the eluent to obtain 3.86 g of (4-hydroxy-phenoxy) acetonitrile as a yellow oil. .

55% -106- Nagasaki Standard _ Standard (CNS) M Specification (Training 7 Public Managers) -------- Wear-(Please read the precautions on the back before filling this page) ·, τ 1. · 517049 A7 B7 V. Description of the invention (104 Dissolve 7.5 g of (4 · -yl-fluorenyloxy) acetic acid in 60 liters of Citico-methyl tiger and cool in an ice bath ', and 3, 88 ml of 70% nitric acid was added dropwise. After 45 minutes, the mixture was poured into ethyl acetate, washed with brine, dried (MgS04), and evaporated to dryness. The crude product was extracted with ethyl acetate. / Hexane (I ·])} glutamic acid was purified by gelatin chromatography to obtain 5.45 g of (4-alkyl-3-acyl-phenoxy) acetonitrile as a yellow solid f. The point is 113.1-114.11. 3. Preparation of (4 -fluorenyl-3_nitro-phenoxy) ethyl wax 〇2N \ ^ \ / 〇

K2C〇3 DMF 80%

A mixture containing 6.0 g (4-¾yl-3-nitro.phenoxy) acetonitrile, 50 ml of n, N-dimethylformamide, 12.8 g of potassium carbonate, and 5.8 g of benzyl bromide Homogenize the mixture and heat at 70 ° C for 22 hours. The mixture was cooled to room temperature, poured into ethyl acetate, washed with water, washed with 1N sodium hydroxide, washed with water again, dried (MgS04), and evaporated to obtain 7.06 g of a yellow-brown solid. (4-Benzyloxy-3-nitro-phenoxy) acetonitrile. Preparation of 4 · (3-Amino_4_Hanoxy-phenoxy) ethoxyl

XN, · Approval-(Please read the precautions on the back before filling out this page)-Order J .. Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Bn〇

SnCl2 · 2 H20 -— &gt; EtOAc 90%

Bn〇4 A solution containing 6.9 g (4-benzyloxy-3-nitro · phenoxy) acetonitrile, 200 ml of ethyl acetate, and 27.4 g of tin (II) chloride dihydrate at room temperature Stir for 7 hours, pour into ethyl acetate, and add a saturated solution of sodium bicarbonate. -107 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -517049 A7 B7 V. Description of the invention (105 to Ethyl acetate was extracted twice, dried (MgS04), and evaporated to obtain 6.0 g of (3-amino-4-fluorenyloxy-phenoxy) ethyl acetate. 5. N- (2-fluorene) Preparation of oxy-5-cyanomethoxy-phenyl) methanesulfonamide ° \ ^ cn CH3SO2CI CH3S〇2NH \ ^ \ / o ^^ cn. Pyridine

Bn〇. Pyridine 47%

Bn〇 The solution containing 5.9 g (4-benzyloxy-3_nitro-phenoxy) acetonitrile and 24 ml of pyridine was cooled in an ice bath, and treated with 3.46 g of methanesulfonyl chloride at a drop rate. Mix for 1 hour. The mixture was treated with 5 ml of water, the ice bath was removed and stirred at room temperature for 30 minutes. The mixture was poured into ethyl acetate, ice was added, acidified with concentrated hydrochloric acid, washed with brine, dried (MgS04), and evaporated. The residue was purified on a silica gel eluting with ethyl acetate / hexane (2: 5) to obtain 3.57 g of N- (2-benzyloxy-5-cyanomethoxy-phenyl). Methyl Si amine. 6 · N- 丨 2-Benzyloxy-5- (4,5-dihydro-fluorene-imidazol-2-ylmethoxy Vphenyl group

CH3S〇2NhL ^ \ ^ 0 v ^ CN ethylenediamine CI ^ SOsNH ^^^ / O

BnO ^ (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Me3Al toluene 47%

Bn〇 &gt;

A solution of 1.49 g of ethylenediamine in 20 ml of toluene was cooled in an ice bath, and 12.4 ml of a 2 M trimethylaluminum solution in toluene was slowly added. The ice bath was removed, and the mixture was stirred at room temperature for 1 hour. Contains 2.73 g of N- (2-benzyloxy-5-cyanomethoxy-phenyl) -methanesulfonamide and 40 ml of toluene 108. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 A7 B7 V. The mixture of the description of the invention (106). The above fluorene complex is treated and heated to 125 ° C for 14 hours. The mixture was cooled to room temperature, diluted with diazomethane, and the excess reagent was decomposed with methanol, filtered through a celite layer, and evaporated to dryness. The residual field was purified by silica gel chromatography eluting with ethyl acetate / methanol / isopropylamine (96: 2: 2) to obtain .43 g of N- [2-fluorenoxy -5- (4,5-dihydro-1H-imid-2-ylmethoxy) -phenyl] methylenepyrazine. Preparation of L__Di 氤 _1 氤 -imidazole-2-Vomethoxy_2-hydroxy-phenylmethylene methylamine (Please read the notes on the back before filling.

MeOH 59% mp 202.5-202.9 ° C Pack-: Write this page) Printed by the provincial Consumer Standards Cooperative of the Central Bureau of Standards 900 mg N- [2-benzyloxy-5- (4,5-dihydro A solution of -1H-imidazol-2-ylfluorenyloxy) -phenyl] formamidine in 40 ml of methanol, 900 mg of ammonium formate and 450 mg of Pearman's nian (s) catalyst ( Treated with 20% Pd) and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, the catalyst was filtered off 'and the mixture was evaporated to dryness. The mixture was purified by dreamstone condensing chromatography with acetic acid / methanol / isopropylamine (85: 1 0: 5) to obtain 404 g of free test, which was converted into salts and hydrochlorinated. N- [5- (4,5-Dihydro · 1Η · Mimid-2-ylmethoxy) _2-hydroxy-phenyl] methanesulfonamide, melting point 205 5-202.9 ° C Example 2K Hydrogenation of N- 丨 5- (4,5-Difluorene_1H-imidazol-2-ylmethylamino V · 3-gas-phenyl] Methanesulfonamide Preparation-109-

、 1T -1 · This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297mm) 517049 A7 B7 V. Description of invention (107 CH3S〇2NKSs ^

Hydrogenated N- [5- (4,5_dihydro-1H-imidazolylmethoxy) -3_gas_phenyl] methylamine amine 1. · (3,5-diundityphenoxy) ethyl Loss of compensation

BrCH2CN

, CN

Dissolve 3,5 · second base test (15.0 g) and 10.75 g of bromoacetonitrile in 85 liters of 2-butanone and treat with 33.78 g of potassium carbonate. The heterogeneous mixture was stirred and heated at 70 ° C for 5 hours, cooled to room temperature, poured into ethyl acetate, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with dichloromethane / hexane (3: 1) to obtain 124 g of (3,5-dinitrophenoxy) as a pale yellow solid. Acetonitrile. 2 · (3-Amino-5-nitro · phenoxy) acetonitrile preparation-° \ ^ CN 仏 〇2N ^, / CN ------- 10 ^ II (Please read the precautions on the back first (Fill in this page again.)

HoAc No. 32% NH2 Dissolve (3,5-dinitrophenoxy) acetonitrile (12.5 g) in 150 ml of warm acetic acid and add 9.4 g of iron powder. When an exothermic reaction occurs, the mixture is stirred and heated to 50 ° C. The mixture was heated at 50 ° C for 2 hours. Cool the mixture to room temperature, 'pour into ice water' and 'filter' and solid residue -110- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 517049 A7 B7 V. Description of the invention (108 dissolved in In ethyl acetate, dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was purified using a silica gel column eluting with ethyl acetate to obtain 7.76 g of (3-amino-5 -Nitro-phenoxy) acetonitrile.

nh2

55%

, CN

3. Preparation of (3-chloro-5 · nitro-phenoxy) acetonitrile 9.05 g of copper (II) chloride in 100 ml of acetonitrile and 10 ml of a dark suspension of third butyl nitrite were stirred, and Heat to 60 ° C. A solution of 10.84 g (3.amino-5-nitro-phenoxy) acetonitrile in 100 ml of acetonitrile was added to the mixture. After 15 minutes at 60 ° C, the solvent was evaporated, water was added, and the mixture was extracted twice with ethyl acetate, dried (MgS04), and evaporated. The residue was purified by silica gel chromatography eluting with dichloromethane to obtain 9.89 g of (3-chloro-5-nitrophenoxy) acetonitrile as a milky yellow solid. 4. Preparation of (3-Amino-5-Gas-Phenoxy) Acetonitrile 0, / CN (Please read the precautions on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

A solution of 8.23 g of (3-chloro-5-nitro-phenoxy) acetonitrile in 150 ml of ethyl acetate was treated with 34.9 g of tin (II) chloride dihydrate, and the solution was heated at 70 ° C. Heat for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, and diluted with 'Winner's saturated liquid test.' Two samples were obtained with ethyl acetate and ethyl alcohol. -111-This paper size applies to Chinese National Standard (CNS) A4 specifications ( 210X297 mm) 517049 A7 B7 V. Description of the invention (109) 'Human, dried (M g S Ο 4), and evaporated to dryness / sintering (35:65) as silica gel chromatography as the eluent Purification by surgery yielded 4 42 g of (3-amino-5-gas-phenoxy) acetonitrile as a milky yellow solid. —- &amp; Gasification N- 丨 5 · Γ4 · 5-dihydro_1Η · imidazole-2-a certain gas thing phenyl] methanesulfonamide, 〇 \ / CN CH3S02Nh ^ H2N \

οι Hydrochloric acid was prepared in a similar manner to that described in Example 1, except starting from (3-amino-5_chloro-phenoxyacetonitrile. [5_ (4,5_dihydroimidazole · 2_ Methylmethoxy) -3-gas-phenyl] methanesulfonylamine, melting point 176 5-18-055 «c. Example 2L I hydrogen fluoride-1H-imidazol-2-ylmethylamino V5-1-mochi 1

HCl —.— ^ ---- i || N Clothing ------ Order ------ (Please read the notes on the back before filling this page) The method is similar to that described in Example 1, except that 3-fluoro-5-nitro-phenol prepared from Degiorgi et al., Biill. Soc. Chim Fr Π 937) 1636, Preparation of hydrochlorodihydro · m_ imid-2-ylmethoxy) -5-fluoro-phenyl] methanesulfonamide, melting point 203.2-204.2 ° C 〇 Example 2M Oxygen: Oxidation NP- (4, 5-Difluorene-1H-pyridylcarbyl) -5-methyl ^ 112- The paper size applies to the Chinese National Standard (CNS) A4 (21〇297mm) 517049 A7 B7 5. Description of the invention (110) Preparation of mesosulfonamide printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ch3s〇2n

HC1 was similar to the method described in Example 1, except starting from 3-methyl-5-nitro-fluorene prepared according to Nieie et al., Cie! N · Ber ._ (1882) jjj2986 , Hydrogenated hydrazone [3- (4,5-dihydro-1H-imidazol-2-ylmethoxy) -5 · methyl-phenyl] methanesulfonamide, melting point 207 8-2. 8 6. (3.

Example 2N Tomb gasification N-丨 6 -gas-3- (4.5-dichloro-1H-Weijun-2-ylmethoxy) -2-methyl-phenyl 1 methylamine is also an alternative Preparation of __Amino-4-Ga-Zheng-cresolol Preparation of 3-Amino-4-Ga-o-toluene (60 g) dissolved in anhydrous methane acid (300 ml) with stirring In the solution, N-gassuccinimide (68 · 3 g, divided into five equal parts) was added over 2 hours and 10 minutes, and the reaction temperature was maintained at 1 ° -12 ° c by using a cooling bath. The dark mixture was allowed to stir overnight and warmed to. It was then added to the milliliter of water with stirring (final temperature approximately 51 ° C). Concentrated ammonium hydroxide (370 ml) was added with stirring, and the reaction temperature was maintained at 50.6x by using a cooling bath. The product was crystallized at 50 · 53 C when the total bundle was added. The product slurry was cooled to the temperature of the ice bath and held for 1 hour. The product (isolated via filtration, yield 70.5%) was washed with ice water and dried at 50 ° C. (： Dried in the air below, the area corrected by the relative reaction coefficient-normalized HPLC shows a purity of 98.44¾. It contains only -------- ^ · equipment ------ order --- --- AW (Please read the notes on the back before filling this page) 113-

517049 A7 B7 V. Description of the invention, 111--8% 6-chloro isomer and 0.68% 4,6-dichloro impurity. Isopropanol-water was recrystallized from carbon treatment to obtain a purified product (143-144 ° C) with a purity of 98.44%. The recovery rate was 94%. Preparation of 1 · (2-methyl-3-amino-4-chlorophenoxy) acetonitrile ^, 〇Η

TsO ^^ CN Η2N \ χ ^^) tBu, THF, DiMF

MeW / ° \ / CN Printed KOtBu, THF by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, dissolved in 4-1 potassium tetrabutoxide (KOtBu) (7.15 g) in 4; 1 tetragas (THF) / 12 ml Ν In a solution of N-dimethylformamide (DMF) (36 liters), 3-amino-4-chloro-zheng-cresol (10.0 g) was dissolved in the same solvent system (20 亳L) solution was added at a rate such that the reaction temperature did not exceed 25 ° C. After 30 minutes, a solution of cyanomethylsulfonium sulfonate (13.00 g) in 4: 1 tetragasfuran / 4 ml of N, N-dimethylformamide (16 ml) was slowly added to the benzene oxide In the solution, the temperature is maintained at or below 25 ° C. The resulting solution was stirred for 3 hours, at which time TLC analysis indicated that the reaction was complete. The crude mixture was partitioned between toluene (100 ml) and water (100 ml), and the aqueous phase was extracted with 50 ml portions of toluene. The combined organics were washed with 1N NaOH and water, and then concentrated to an oil (81 g, 97.6% crude yield). The crude product was typically directly subjected to the next step without purification. Alternatively, the product can be recrystallized from a mixture containing toluene and hexane to obtain a pale yellow-brown crystalline solid (purity &gt; 98% by HPLC). 1: __Gas-3-Cyanomethyl Gas Odor_2_Methylphenyl) Methanesulfonamide ---------! (Please read the precautions on the back before filling in this page j -Order · -114 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (21〇 &lt; 297 mm) 517049 A7 B7 V. Description of the invention (112

.JU

MsCl, py

MsH

EtOAc, THF, PhMe

Me

, CN Add methanesulfonyl chloride (4.5 ml, 6.7 g) to (2: methyl-3-amino-4-chlorophenoxy) acetonitrile (11.5 3 g) and dissolve in toluene (PhMe) (60 ml) of the solution, and the resulting solution was warmed to 35-40 ° C. Then pyridine (py) (4.7 ml, 4.6 g) was added slowly over 2 hours. The resulting solution was cooled to a temperature of E and stirred for 24 hours. The crude product mixture was then partitioned between N-hydrochloric acid (100 ml) and a mixture containing ethyl acetate (300 ml) and tetrahydrofuran (100 ml). The organic phase was washed with water and then concentrated to about 200 ml, which resulted in crystallization of the desired product. The white crystalline product was collected, washed with toluene and dried to obtain 10.40 g (65.1% yield) of N- (6-gas-3-cyanomethoxy-2-methylphenyl) methanesulfonamide (as HPLC shows purity &gt; 97%). This material can be recrystallized from isopropanol if necessary. . 4 · Hydrochloride 1 ^-"6-Ga-3- (4,5-dihydro-11 ^ -imidazol-2-ylfluorenyl)-2-methyl-benzyl 1methanesulfonamide Preparation of iH ^ HCI, OEt — ^ -I! Ti (Please read the notes on the back before filling out this page) J .. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

° V / CN EtOH, HCl MsHN αζαΓ

Me ΝΗ ·, nh2 1) η〆 —IvleOlT 2) iPr0H / H20 recrys.

-115- • HCl This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 517049 A7 _ B7 V. Description of the invention (113 Gasification of milk into N-(6 -Ga-3 -Gamethoxy) 2-methylphenyl) methanesulfonamide (10.0 g) in a suspension containing a mixture of dichloromethane (100 ml) and ethanol (25 ml) for 5 minutes (to reach saturation) Keep below 15 ° C. Stir the resulting mixture for 2 hours at Baoyuan temperature, during which the intermediate hydrogenated sulfonium imidate is precipitated. The excess hydrogen chloride is removed from the reaction vessel, and The resulting slurry was completely dissolved by adding methanol (40 ml). Then this solution was added to a solution of ethylene diamine (2.4 ml, 2.2 g) in methanol (40 ml) to keep the temperature below 25. (: In 5 minutes, the desired product salt starts to spontaneously, and the reaction mixture is precipitated from the reaction mixture. After 1 hour, the solution is distilled to contain isopropyl alcohol and water (100 ml in 4: 1). ) The mixture was replaced, and the crystalline product was collected. After washing with isopropanol, the solid was dried to obtain 8.69 g of hydrochlorination! ^-[6-Chloro-3- (4,5-dihydro-1-H-imidazol-2-yl-methoxy) -2-methylphenyl] methanesulfonamide ( Yield 68 · 3%, purity shown by HPLC 98.6%). This material can be recrystallized from 4: 1 isopropanol / water as needed. Example 3 Imidazol-4-ylfluorenyl) -2-methyl- Preparation of Phenyl 1 Methanesulfonamide H CH3 (Read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Bureau of Standards of Didi H CH3 Ν Ν · [3- (1 Η-imidazol-4-ylmethyl) -2-methyl-phenyl] methanesulfonamide

DMF 〇2M Cl + NaCN + Nal-

116- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 517049 A7 B7 V. Description of the invention (114) The 1-gas methyl-2-methyl-3-nitro-benzene (25 g ) Dissolved in 25 ml of N, N-dimethylformamide. 1089 grams of sodium cyanide (MaUinckrodt, Paris, Kentucky) and 0.4 grams of sodium sulphide (Mallinckrodt) were added to the mixture. The heterogeneous mixture was heated to 80 ° C for 21 hours. The reaction mixture was cooled to room temperature, poured into ether, washed several times with water extraction, dried and evaporated. The residue was purified by flash chromatography on a silica gel and eluted with two gas methane to obtain 16.83 g of (2-methyl-3-nitro-phenyl) acetonitrile as a milky yellow solid.

10% Pd / C H2

(2 · methyl-3_nitro-phenyl) acetonitrile (16.6 g) was dissolved in 400 ml of ethyl acetate, and 0.83 g of 10% palladium on carbon (Degussa type) was added; and The reaction mixture was placed under 50 pounds per square inch of hydrogen on a parr shaker for 4 hours. The catalyst was filtered off; the solvent was evaporated; and the residue was purified by flash chromatography on a stone gel with acetic acid: hexane (2: 3), resulting in 11.1 g of white (3-Amino-2-methyl-phenyl) ethyl solid (Please read the precautions on the back before filling this page) One pack · Order J ·. Printed by the Consumer Standards Cooperative of the Central Standards Bureau of Didi Ministry

Η π CH3 CN + CH3S02C1… than 疋, (3-amino-2-methylphenyl) acetonitrile (U.! G) was dissolved in 80 ml of pyridine. The solution was cooled in an ice bath, and 3 g of methanesulfonium gas was added. Remove the reaction mixture from the ice bath and stir at room temperature for 30 minutes; 117- this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 A7 B7 V. Description of the invention (115 1 〇靟 L of water was added, and the mixture was stirred at room temperature for 30 minutes, poured into ethyl acetate (EtOAc), 'washed with ice hydrogen acid, washed with water, dried, and evaporated' to obtain 16.1 g of a pale yellow solid Ν · (3-cyanomethoxy · 2-methyl-phenylmethanesulfonamide. H CH3 ch3so2

CN + DEAL H CH3 CH〇 Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, N- (3-cyanomethoxy-2-methyl-phenyl) _methanesulfonamide (3.75 g) was dissolved in 50 ml of tetrahydrofuran And placed in an ice bath and cooled under a nitrogen atmosphere. To this mixture was added 67 ml of 1 M diisobutylaluminum hydride (DIBAL) dissolved in tetrahydrofuran. The mixture was stirred at 5 ° C for 75 minutes. The excess reagent was decomposed with methanol and the solvent was evaporated. The residue was treated with EtO Ac, washed with ice 1M hydrogen acid, extracted with brine and dried, and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with methanol: dichloromethane (5:95) to obtain 1.1 g of N_ [2-methyl-3- (2-oxygen) as a yellow oil. -Ethyl) · phenyl] formamidine. N- [2-methyl-3- (2-oxo-ethyl) -phenyl] methanesulfonamide (1.08 g) was dissolved in 30 ml of absolute ethanol, and .02 g of isocyanation (P-fluorenyl) -methyl (TosMIC) was added with 23 mg of sodium cyanide. The reaction mixture was stirred at room temperature for 14 hours. The precipitated solid was filtered to obtain 1.24 g of N- {2-fluorenyl-3- [4- (fluoren-4_fluorenyl) -4,5_dihydro · humazole-5-methyl as a yellow-brown solid. ] -Phenyl} formamidine. CH3S〇2

H CH3

-118- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) 517049 A7 B7 V. Description of the invention (116 N- {2-methyl-3- [4- (芴 · 4 · 飒 基) ) -4,5-Dihydro · Hemazole_5-methyl] _phenyl} methylpyridamine (1.2 g) suspended in 15 ml of 2M dissolved in 2-propanol gas' as for the sealed tube , And heated at 100 ° C. for 5 hours. The mixture was sacrificed and the residue was purified by flash chromatography on a lithotripsy gel with methanol: dimethylformate (5.95), and 437 mg was obtained, which was crystallized from ethanol to give 249 mg of N- [3- (1H-imidazol-4-ylmethyl) _2 · methyl-phenyl] formamidine, melting point 223.8-224.4 ° C.

Example 3A V2.5 · dimethyl-benzyl 1-methanesulfonyl N- 丨 oxazole-4-ylmethyl -------- mt-- (Read the precautions on the back before reading (Fill in this page) Preparation of amines ch3s〇2n.

, 11 In a manner similar to that described in Example 3.3, except from the 1-fluoromethyl · 2,5—-prepared according to Winchester et al., Heterocyclic Chemistry (1975) U: 547 N- [3- (3Η-imid-4-ylmethyl) -2,5-dimethyl-phenyl] methanesulfonamide, prepared from the acid i8l l_182.9 ° C Example 4 N- [5- (3H-imidazol-4-ylmethyl) -2-methyl-phenyl 1 methanesulfonamide

This paper size applies Chinese National Standard (CNS) A4 specification (21 〇 × 297 mm) 4 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517049 A7 B7 117 1. Description of the invention (N- [5- (3 Η-imidazole- 4-Methyl) -2-methyl-phenyl] methanesulfonamide preparation m 〇2 team

Ci Acetone + LiBr-—

CH3〆 ^ CHz 4-chloromethyl-1_methyl_2_nitro-benzene (5 g) was dissolved in 50 ml of acetone 'and 23.4 g of lithium bromide was added. The reaction mixture was heated at reflux for 18 hours. The solvent was removed by evaporation, and the residue was dispersed in hexane to obtain 5.3 g of 4-bromomethyl-1-methyl-2-nitro-benzene as a tan solid.

F Pack-ί Please read the precautions on the back before filling out this page) Order _ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ) -4,5 -Diaza-Weijun-1 Diamine (5.03 g) (prepared by Ngochindo, Chem Sn. Pej ^ inj Trans. I. (1990) 1645 (Acquired) was dissolved in 100 ml of tetrachlorofuran, and cooled to -78 ° C in a dry ice-acetone bath; IX · 9 ml of dissolved n-butyl alcohol was added to the mixture. After the time had elapsed, the reaction mixture was treated dropwise with 5.0 g of 4-bromomethyl-methyl-2-nitro-benzene dissolved in 25 ml of dry tetrazine 7-furan (THF). The mixture was left at 78 ° C for 1 hour and then allowed to warm to room temperature overnight. The mixture was treated with and ammonium chloride, extracted with ethyl acetate, and the combined extracts were washed with and sodium gaseous, dried, and evaporated to dryness. The residue was purified by flash chromatography on a Shixi gel with ethyl acetate: hexane (I: 4) -120 This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) — 517049 A7 B7 5. Description of the invention (Ή8) and 2.39 g of 2- (third-butyl-dimethyl-silyl) _5_ (xinxi methyl-1-methyl-2- Acyl-phenylfluorenyl) _Mijun-1_ Dimethylamine. (CH3) 2NS〇2 ^^ TBDMS 10% Pd / C (CH3) 2NS〇, 2 〇2N \ Ύ Degussa type ^ '

TBDMS H2 / EtO Ac ch3 '\ ^ ch3 will be 2- (third-butyl-dimethyl-silyl (heart'methyl · ^ methyl · 2 · nitro-privatemethyl) -Mijun-1- Dimethylamine hormonate (2.32 g) was dissolved in 125 ml of ethyl acetate and 0.50 g of 10% palladium (Pd / C) was added. The reaction mixture was placed at 44 psi in parr The hydrogenation was performed on a shaker for 14 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate: hexane (1: 3) ' 1.05 g of 5- (3-amino-4-methyl-benzyl) · 2- (third-butyl-dimethyl · silyl) _imidazole · 丨 -sulfonic acid difluoride as a white solid was obtained Amidine. (CH3) 2NS〇2 H2N \ ^ \

TBDMS CH3S02C1 pyridine then hckh2o ch3so2

(Please read the precautions on the back before filling out this page) k Binding · Ordering Staff Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, Yin Fanjiang 5- (3-Amino-4 -Methyl-Phenyl) -2- (Section Tri-butyl-dimethyl-pyridyl) · imidazole-1-sulfonic acid dimethylammonium amine (1.02 g) was dissolved in 7 ml of pyridine, cooled in an ice bath, and 0.34 g of formazan continued _ Chlorine added. After the reaction mixture was removed at 5 ° C for 1 hour, 2 ml of water was added, and the mixture was evaporated to a small volume, dissolved in ethyl acetate, washed with water, dried, and evaporated. The remaining 0.8 5 grams of ochre oil. The residue was dissolved in 25 ml of methanol, treated with 2 ml of 6M hydrochloric acid, and heated at 70 ° C for 16 hours. Solvent -121 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 Η

A7 B7 V. Description of the invention ϊ19) Evaporate, and purify the residue by flash chromatography using acetic acid: methanol: isopropylamine (92 ·· 5: 3) as the coagulant on Shi Xishi. 42 g, which was crystallized from ethanol to obtain 0.31 g of N- [5- (3Η-imidazol-4-ylmethyl) -2-methyl-phenyl] sulfonamidine, melting point 170.1-170.4 ° C. Example 5 Preparation of 1 gasified N_f3- (4,5-dihydro_1H-furazol-2-ylmethanamine 1 methanesulfonamide · CH3S〇 hydrogenated N- [3- (4,5-di Argon-1H-imidazol-2-ylmethyl) -phenyl] methanesulfonamide (Please read the precautions on the back before filling this page)

, \ = The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy printed 1-chloromethyl-3-nitro-benzene (5 g) and 4.28 g of sodium cyanide, dissolved in 15 ml of water and 50 ml of dioxin In a mixture of alkanes, and the biphasic mixture was heated at 100 ° C. for 12 hours. Dioxane was removed by evaporation, and the aqueous solution was extracted with methane. The organic extract was washed with brine, dried, and evaporated. The residue was purified by flash chromatography eluting with EtOAc: hexane (1: 4) to give 2.86 g of (3-nitro-phenyl) ethyl wax as a tan solid, m.p. 51.7 -52.7 ° C.

-122- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) 517049 A7 B7 V. Description of the invention 120 Dissolve (3-nitro-phenyl) acetonitrile (2.7 g) in 50 ml of acetic acid Ethyl acetate, and treated with 19.5 g of vaporized tin (Π) dihydrate, and stirred at room temperature for 72 hours. The mixture was diluted with ethyl acetate and treated with a saturated sodium bicarbonate solution, separated, and extracted with ethyl acetate. The extracts were combined, dried and evaporated, leaving 2.1 g of (3-amino-phenyl) · acetonitrile as a yellow-brown solid. ·

ch3so2ci ch3so2

(3-Amino-phenyl) acetonitrile (2.9 g) was dissolved in 8 ml of pyridine, cooled in an ice bath, treated with 2.6 g of methanesulfonyl chloride, and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with hydrochloric acid, then brine, dried over magnesium sulfate, and evaporated to give 26 g of ^-(3-cyanomethyl_phenyl) -methanesulfonamide. Milky yellow solid. Η CH3S〇2 + EtOH + HC1 CH3SO2

(Please read the precautions on the back before filling out this page) ^ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, N- (3-cyanomethylphenyl) _methanesulfonamide (1.5 g) Dissolve in 50 ml of dichloromethane and 0.49 ml of ethanol and cool in an ice bath. Hydrogen chloride gas was added with aeration until a saturated solution was formed. The mixture was stirred at room temperature for 1 hour and then at room temperature for 14 hours. The solvent was evaporated to obtain 2.2 g of ethyl 2- (3-methylpyridinamido-phenyl) · acetamidate as a white solid. -123-This paper size applies Chinese National Standard (CNS) mm 517 049049 A7 B7 V. Description of the invention / 121

Η I

+ H2NCH2cH State K ^ J NH -HCI CH3S〇2

H · HCI Dissolve 2- (3-sulfanyl g-amino-phenyl) -acetamidoacetaldehyde (2.1 g) hydrochloride in 30 ml of ethanol, treat with 0.51 g of ethylenediamine, and Stir at room temperature for 16 hours. The solvent was evaporated, and the residue was purified by flash chromatography on a silica gel with methanol: dichloromethane (15:85) as the eluent solvent to obtain a free base by adding 1M gas in ether. Hydrogenation, converting it into hydrogen chloride salt, hydrochloride N- [3- (4,5-dihydro-1H · imidazol-2-ylmethyl) -2-tolyl] methanesulfonamide, melting point 194.8- 195.2 ° C. Example 5A Wu: 气 ί ύ 1SI-f 3-(4,5 sided two mice-1Η _ 味 口 坐 · 2-. Dimethyl: phenyl) -2 -methyl-phenyl] (Please read the back Note: Please fill out this page again) Preparation of mesylate Chh

N η · ηοι was printed by the Consumer Cooperative of the Central Bureau of Standards of Didi Ministry in a similar manner as described in Example 5, except that the starting material was 1-chloromethyl-2-methyl-3-nitro-benzene, and Preparation of N- [3- (4,5-dihydro-15--imidazol-2-ylmethyl) -2 · methyl-phenyl] methanesulfonamide hydrochloride, melting point 1 85.3-1 85.5 ° C 〇Example 5B Preparation of hydrogenated N- 丨 5- (4,5-difluorene-1H · imidazol-2-ylmethyl) -2-methyl-phenyl 1 methystilamine -124 Applicable to paper size China National Standard (CNS) A4 specification (210X 297 mm) 517049 A7 B7 V. Description of the invention (122)

H-HCI was prepared by a method similar to that described in Example 5, except that the starting material was 1-chloromethyl-4-methyl-3-nitro-benzene, and N- [5- (4 , 5 · Dihydro-1,1-imidazol-2.ylmethyl) -2-methyl-phenyl] methanesulfonamide, melting point 262-263 ° C.

Example 5C Imperial N- 丨 3-M.5-dihydro · 1Η · imidazole-2-some methyl) -5-methyl-phenyl 1 (Please read the precautions on the back before filling this page) Preparation of formazan

HC1 was prepared by a method similar to that described in Example 5 by the Central Laboratories of the Ministry of Standards and Industry of China, except that it was prepared according to the method described by Makosza et al., Tetrahedron 9 (1984) 40 _:] 863 The obtained 1-bromomethyl-3-methyl · 5-nitro-benzene was started, and N- [3- (4,5-dihydro-1H-imidazol-2-ylmethyl) hydrochloride was prepared. ) -5-methyl-phenyl] methanesulfonamide, melting point 185.3-185.5 ° C.

Example 5D Preparation of hydrogenated N-Γ3-M.5-dihydro-1H-imidazol-2-ylmethyl) -2,6 · dimethyl-phenyl 1methanesulfonamide

The method described in Example 5 is similar, except that according to Goldstein-125- this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 A7 B7 V. Description of the invention (123), Fang ( (Goldstein), et al., J, Org. Chem., (1 984) 16 13 and 1-chloromethyl-2,4-diamidino-3-nitro-benzene starting method, and N- [3_ (4,5_dihydro-1H-imidazol-2-ylfluorenyl) -2,6-dimethyl ^ phenyl] methanesulfonyl chloride is obtained, with a melting point of 245-245.7 ° C. Example 5E Hydrogenation of N- 『3- (4,5-Difluorene_1Η · imidazol-2-ylmethyl, a certain two-art technique, the preparation of benzyl 1-methanesulfonamide, ch3so2n

A method similar to that described in Example 5 was used, except that 1-methyl-2,5-dimethyl was prepared according to the method of heterocyclic chemistry (1975) j ^: 547 from Winchester et al. N- [3_ (4,5-dihydro-1H-imidazol-2-ylmethyl) · 2,5-dimethyl-phenyl] Methanesulfonamide, melting point 177-178.5 ° C. Example 5F · Preparation of N- 『3- (4,5-dihydro-1H-imidazolylmethyl) _2,4-di-phenyl 1methanesulfonyl chloride, please read the note on the back first Please fill in this page for the deposit) Order Φ1 of the Central Consumers Bureau of the Ministry of Economy Staff Consumer Cooperatives

ISU H ^ HC1 Hydrogenated N- [3- (4,5-dihydro_1Η-imidazol-2-ylmethyl) _2,4_dimethylphenyl] methylenepyrazine 126- This paper is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 517049 A7 B7 V. Description of the invention (124 CH3, CH3.co2h +

It was cooled in an ice bath and treated with 8.9 ml of 70% nitric acid and then with 14 ml of concentrated sulfuric acid. The ice bath was removed and the mixture was stirred at room temperature for 22 hours. The mixture was poured into ethyl acetate, washed with water several times, dried, and evaporated to obtain 17.2 g of 2,6-dimethyl-3-nitrobenzoic acid. The melting point was 115 9-116.5〇C 〇CH3 〇2N ^ \ / C02H 2,6-Dimethyl-3 · nitro: il pfran was added and 165 ml of 1M borane dissolved in tetrahydrofuran was added. Give the dagger pan at 75 C for 4 hours. The mixture was cooled to room temperature, and the solvent was slowly decomposed with water, and the solvent was evaporated. The residue was treated with acetic acid acetate 'with 1 M hydrochloric acid, then washed with water, dried, and evaporated. 8.71 g (2,6-dimethyl · 3-nitrophenyl) _methanol, dissolved Points 94.5-9ό 1V.

Employees' Cooperatives, Central Standards Bureau, Ministry of Economic Affairs, India

PBγ3

Eridine (2,6β-dimethylnitrophenyl) -methanol (7.3 g) was dissolved in 73 liters of lactone, and 3 · $ 龛 liter ratio was added. Place the mixture in an ice bath -127 paper size ^ iiii? T ^ iiT7 ^ F (l10x297 mm) (Please read the precautions on the back before filling this page)

517049 V. Description of the invention (125 Cooling and ageing ancient — ^ ”· Wuering Linghua brick was added and stirred at 5 ° C for 30 minutes. ^ ^ Mouthpiece was poured into ethyl acetate, washed with brine Twice, dried over magnesium sulfate and evaporated to dryness to give 8.3 g of 2-bromomethyl_1,3_dimethylI-4-nitrobenzene as a milky yellow solid. Ch3 Br ch3S02nk ^ \ ^^ ^ — To J]

Η HC1 is similar to the method described in Example 5 except that starting from 2-bromomethyl-1,3-dimethyl 4-nitro-benzene, the hydrochloride N- [3- (4, 5_dihydro-1Η-imidazolium 2-ylmethyl) _2,4-dimethylphenyl] methanesulfonamide, melting point 107-124t. Example 5G Preparation of H-1H-imidazol-2-ylmethyl) _2- 氲 its ^ sulfamethoxamine «Drapery-i · (Please read the precautions on the back before filling this page)

, 1T cH3S〇2n

氲 Gasification Ν_ [5 · (4,5-Difluorene · 1Η-imidazole-2 · ylmethyl &gt; 2-fluoro · phenyl] Pyridoxamine ΙΦ. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

ΒΓ2

150 ° C

, CH2Br at 150 ° C, slowly add 3.65 liters of bromine under the sun light, and at 5 o'clock, add 1 · fluoro-4-methyl-2 · nitro-benzene (10 grams) Cool the M brown mixture to 50 t, and pour it into 125 ml of original paper ruler 128- 517049 A7 B7 V. Description of the invention (126. Cool in an ice bath 'filter 1 0.1 g of 4-bromomethyl-1-fluoro-2-nitrobenzene was obtained as white crystals.

〇2N \ ^ \ / CH2BrFXJ-

I · HC1 H was prepared by a method similar to that described in Example 5 except that 4-bromomethyl-i · fluoronitro-qin was used to prepare hydrofluorinated N- [5- (4,5-dihydro -1H-imidazol-2-ylmethyl) -2-fluoro-phenyl] methylenepyrazine, with a bright point of 205.2-205.7 ° C. Example 5: ΗN- 丨 5 · M, 5-dihydro-1Η-imidazol-2-ylmethyl) -4_fluoro-benzyl 1 methylamine amine preparation CH3S〇2NHv ^ a ▲ N.

-------- · Installation-- (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs $ ί HC1 In a similar way to that described in Example 5, but from the root摅 Started from 2-bromofluorenyl-1-fluoro-4-nitro · benzene prepared by the method described by O'Neill et al., J. Med. Chenu ^ (1994) U: 1362 , And prepared N- [3- (3,4-dihydro-1H-imidazol-2-ylmethyl) _4-fluoro-phenyl] methanesulfonamide hydrochloride with a melting point of 245.4-245.7 ° C. Example 51 Preparation of hydrogenated N- 丨 2_gas-3- (4,5-dihydro-1H · imidazol-2-ylmethyl) -phenyl-1methanesulfonamide

-129- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) J .. 517049 A7 B7 V. Description of the invention (127 In a similar way to that described in Example 5, Uneme) et al., Biosci. Biotechnol. Biochem., (1992) 56 2023, starting with 1-bromofluorenyl-2.chloro-3-nitro-benzene, and hydrogenated N- [2-Chloro-3- (4,5-dihydro-1fluorene-imidene-2 · methylfluorenyl) _phenyl] methanesulfonamide, melting point 199.9-201.0 ° C. Example 5J · 1 chloride N_ [5- (4,5-Dihydro · 1Η · imidazole-2-somemethyl) -2-Ga-benzyl 1methanesulfonamide ch3s〇2n IXrf. HCl In a similar manner to that described in Example 5 Starting from 4-bromomethyl-1-chloro-2-nitro-benzene prepared according to the method described by Kelley et al., I. Med. Chem., (1989) 32: 1757 N- [5- (4,5-dihydro-1H-imidazol_2-ylmethyl) -2-chloro-phenyl] methanesulfonamide hydrochloride was prepared, with a melting point of 238.9-240.4 ° C. Example 5K Hydrochloric N- 丨 3 -Yi-5 -Difluorene-Chloro-2-ylmethyl) -phenyl If-— — — — — — If II (Please read the precautions on the back before (Write this page) Order J .. Preparation of printed amines by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. CH3S02NH \ ^^^^ N ^ U V. HO IH Br Hydrochloride N- [3-Bromo_5- ( 4,5-Dihydro_lH-imidazol-2-ylmethyl) -phenyl-pyridamine-130- This paper size applies to China National Standard (CNS) A4 (21〇297297 mm) 517049 A7 B7 V. Description of the invention (128)

Falling liquid 'was treated dropwise in an ice bath with 3.58 g of sodium nitrite dissolved in 10 ml of water. The mixture was then treated simultaneously for 1 hour with 681 g of copper oxide ⑴ and 3 1 · 4 ml of hypophosphorous acid. Pour into ice water, extract with ether, wash with water, dry over magnesium sulfate, and evaporate to dryness. The residue was purified by flash column chromatography on a silica gel using ethyl acetate / hexane (1: 9) to obtain 7-73 g of 1-bromo-3-fluorenyl-5-nitrate. Benzene. (Read the precautions on the back before filling this page)

, 1T Printed by the Consumer Cooperative of the Central Standard Bureau of the Ministry of Economic Affairs, 7.68 grams of 1- &gt; stinky 3-methyl-5-nitrobenzene, 6.64 grams of N-bromosuccinimide, 86 mg of benzamidine peroxide In 100 milliliters of a solution of tetragasified carbon, heated at 90 ° C for 16 hours, cooled to room temperature, filtered, and the filtrate was evaporated to obtain 11 g of 1-bromo-3 which is a ocher, partially crystalline oil. -Bromomethyl-5 · nitrobenzene. This oil was used without purification.

A method similar to that described in Example 5 except that starting from 1-bromo-3-bromomethyl-5-nitro_benzene was used to prepare a pass-emulsified N- [3_brook- 5- (4,5- Diazo-lH-taste-2-ylmethyl ^ phenyl] methanesulfonamide, melting point 216.9-217.5 ° C. -131-This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 517049

、 Explanation of the invention (129 Zhijin, Example 5L, Imidazole_2_a certain methyl group) _2_Methoxy · Benzylamine Preparation

HC1 wind SL N- [3- (4s-with ιττ, monol-1H-imidazol-2-ylmethyl) -2_methoxy-based] methanesulfonamide

) 2Nv ^^ pC〇2H

DMF

+

CH3I K2C〇3 xh3 Η 3, u Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 15 grams of 2 焱 -based &quot; &quot; The solution was treated with 581 g of iodoformamidine and 56.6 g of carbonic acid, and the resulting heterogeneous mixture was stirred and heated at 45 ° C for 20 hours. G mouthpiece was cooled to H and poured into ether, washed with water and saturated with carbonic acid! f washing, X water extraction washing, drying over magnesium sulfate, and evaporation to obtain 14.2 ^ 2methoxy + nitro-benzoic acid formamidine, which is crystallized into a white g body 0 〇αη3〇2Ννγ ^ \ ^ 〇〇2〇Η3

NaBH4 tBuOH -►

MeOH

Dissolve 14.0 g of methyl 2-methoxy-3_nitro-benzoate in 245 ml of -132 paper towels ^^^^ (〇 灿) 8 4 size (210 \ 297 mm) 1 ' ------ 517049 A7 B7

V. Description of the invention (130-butanol solution, treated with 6.75 g of sodium borohydride, and the heterogeneous mixture was heated to 80 ° C. Methanol (62 ml) was added slowly at a drop rate over a period of 2 hours. After 3 hours at 80 ° C, the solvent was evaporated under reduced pressure at 40 ° C, and the residue was treated with water, acidified with hydrogen, extracted with ethyl acetate, and the extract was washed with brine and dried. And evaporated to dryness. The residue was purified by flash column chromatography on silica gel to obtain 8.3 g of (2-methoxy-3_nitro_benzene) as a brown solid. ) _Methanol. 〇High pBr3 〇2yV ^ ch2ci2 Dissolve 14.7 g (2-methoxynitro_phenyl) _methanol in 40 ml of dichloromethane and 5 ml of pyridine. Cool in an ice bath and slowly add 6-48 grams of phosphorus tribromide. After 45 minutes at 50 Ct, the reaction mixture is diluted with dichloromethane, washed with water, dried, and evaporated to dryness. The residue Purification by flash chromatography on a dream stone gel with ethyl acetate g / hexane (5:95) yielded 73 g of a yellow solid Bu-bromo-3-nitro _2- A &gt; equipment - (Please read the Notes on the back to fill out this page) Order Ministry of Economic Affairs Bureau of Standards employees consumer cooperatives printed t.

CH3SO2N

In a manner similar to that described in Example 5, except starting from ^ bromomethyl_2_methoxy_5 nitro-benzene, N- [3- (4,5-dihydro] hydrochloride was prepared H_imidazole_2 · -133 517049 A7 B7 V. Description of the invention (131ylmethyl) -2-methoxy-phenyl] methanesulfonamide, melting point 216.9-217.5. (: Example 5M-N- Γ5-M.5-Difluorene-1H-Weijun-2

A method similar to that described in Example 5 was performed except that 4-bromomethyl-1-methoxy was prepared according to the method described by Shoesmith et al., T Them. Soc. '(1924) 13 17 Benzene · 2 · nitro-benzene starting, and the hydrochloride N- [5- (4,5-dihydro-1Η-imidazol-2-ylmethyl) -2-methoxy-phenyl ] Methanesulfonamide, melting point 201.2-201.5 ° C. Example 5N Nitrogenation N- "5- (4,5 · diaza-1H-Weijun-2 -ylmethyl) -2-meryl-benzene

HBr Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China printed polyhydrogenated N- [5 · (4,5-dihydro-1H-imidazole-2_ylmethyl) -2-hydroxy-phenyl] methanesulfonamide CH2C12 CH3S02N team. JU V + BBr3 —- Η

HBr will be 420 mg of N · [5 · (4,5 · dihydro-1H-imidazol-2-ylmethyl) -2-methoxy-134- This paper size applies to China National Standard (CNS) A4 specifications ( 210X297 mm) Cantonese first read the French and Italian matters on the back and fill in this page)

HN, Cl 517049 A7 B7 V. Description of the invention (132 -Phenyl) methanesulfonamide (free state base) dissolved in 24 ml of digas methane, cooled in an ice bath, and dissolved in dichloromethane with 10.3 ml of 1M Boron tribromide treatment with methane. Remove the ice bath, stir at room temperature for 3 hours, add methanol, and evaporate. Pass the residue on a silica gel with dichloromethane / methanol / ammonium hydroxide. (85: 5: 3) purified by flash chromatography and crystallized from ethanol / ether to obtain 58 mg of N- [5- (4,5-dihydro_1H-imidazole_2 · yl) hydrobromide Methyl) -2-hydroxy · phenyl] methanesulfonamide, melting point 209-209.5 ° C. Example 50 Hydrochloric N- 丨 3-chloro-5- (4,5-dihydro-lH-imidazole- Preparation of 2-ylmethyl V2_fluorenyl · phenyl l-sulfonamide

Preparation of MsNH L ^ 3-Amino-4-methyl-5-nitro-phenylarsinic acid (Please read the precautions on the back before filling this page)

c〇2h

Na2 &amp; 〇4

Me〇H, H2〇 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

no2 nh2 A method similar to that described in Example 6D for preparing 5-chloro-2-fluorenyl-3-nitroaniline from 5-chloro-2-methyl-1,3-dinitroaniline, and from 4 -Methyl-3,5-benzoic acid was prepared to give 3-amino-4-methyl-5-nitro-benzoic acid. 2. Preparation of 3-chloro-4_methyl-5-nitro-benzoic acid, CO 2H

tBuONO, CuCI2 CH3CN

co2h -135- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 517049 A7 B7 V. Description of the invention (133) It is similar to that described in Example 24 for the use of 2,4-dinitro-3 -Methylaniline to prepare 3-gas-2,6-dinitrotoluene, and 3-amino-4-methylnitro-benzoic acid to prepare 3-gas_4-methyl-5-nitrate -Benzoic acid. 3 · (3-Gas-4-methyl-5-nitrobenzyl V methanol prepared bh3, thf 〇2N \

4 · 2 g of 3-gas-4-methyl-5-nitro-benzoic acid was dissolved in 20 ml of THF, and the solution was cooled to 0 ° C. BH3_THF (28 liters) solution was added at 2 liters each. After 1 hour, the reaction mixture was poured onto 100 g of ice containing saturated NaHC03 solution. The mixture was extracted with diethyl ether (3 × is ml). The extract was washed with brine, dried (MgSO4), filtered and concentrated. The resulting brown oil was sampled on a SiO 2 column dissolved in toluene solution and eluted with 25% ethyl acetate in hexane to obtain 196 g (3_chloro_4_methyl -5_nitrophenyl) fluorenol. ^ ~ Li, CB of methyl-1-chloro-2-methyl-3-nitrobenzene, 4, PhsP

CH2CI2, 0 ° C

(Please read the precautions on the back before filling in this page. J Engine installation · Order i ·. It is printed by N_Methanesulfonyl_6 • as described in Example 10 by the Consumer Consumer Cooperative of the Central Standard Bureau of the Ministry of Li Method for preparing N-methanesulfonyl · 6 · bromomethylxindole by hydroxymethyl adol, and% bromomethyl chloride prepared from (3_chloro_4_methyl-5-nitrophenyl) methanol Methyl nitrobenzene.-~~ Nitromum and B are depleted, 彳 i -136-

517049 A7 B7 V. Description of the invention (134)

NaCN. No. alkane / h2o JU CN Cl A method similar to that described in Example 10 for the preparation of N-methylpyridinyl-6-cyanomethylindole from N-fluorinated acid bromomethyl, and (3-Chloro-4_methyl_5_nitrophenyl) acetonitrile was prepared from 5-bromomethyl · 1-gas-2-methyl-3-nitrobenzene. ^ __ (3_Amino · 5_Gamethylphenyl) acetonitrile

SnCl2-2H20 EtOAc

H2jp ^ CN α ci is a method similar to that described in Example 2 for preparing (3-amino-4-methylphenoxy) acetonitrile from (4-methyl_3-nitrophenoxy) acetonitrile, and (3-Amino-5-chloro · 4-methylphenyl) acetonitrile was prepared from (3-chloromethyl-5-nitrophenyl) acetonitrile. -y- (3-Gas-5-cyanomethyl-2 -methylphenyl) methoxamine Preparation H2j〇 ^ cn Cl

MsCI, pyr, CH2CI2

MsN

# --------- · 装-(Please read the precautions on the back before filling this page)

, 1T 1 ·. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, where Ms = CH3SQ2 is similar to that described in Example 1 for the preparation of N- (3-cyanomethoxy) from (3-aminophenoxy) acetonitrile Method for the preparation of N- (3-chloro-5-cyanomethyl-2-fluorenyl) from (3-amino-5-methyl-4-methylphenyl) acetonitrile Phenyl) Methanesulfonamide. -137 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 A7 B7 V. Description of the invention (135) 8 · Hydrogenated N- 『3-chloro · 5- (4,5-dihydro- Preparation of 1H-imidazol-2-ylmethyl V2-methyl · benzyl 1methanesulfonamide

MsNH ppCN Cl

1. HCI (g), EtOH, CH2CI2 -—- ^ 2. H2NCH2CH2NH2, MeOH

Cl where Ms = CH3S02 is used similarly to that described in Example 1 for the preparation of hydrogenated N_ [3- (4,5-dihydro-1H-imidazol-2-ylfluorenyloxy) from (3-aminophenoxy) acetonitrile )] Phenyl] methanesulfonamide, and N- [3-chloro- hydrochloride is prepared from N- (3 · Ga-5_cyanomethyl-2-methylphenyl) methanesulfonamide 5- (4,5-Dihydro-1fluorene-imidazole-2 · ylmethyl) · 2-fluorenyl-phenyl] methanesulfonamide (melting point 256.2-256 · 7 × :). Example 5P Preparation of N- 丨 3-bromo-5- (4,5 • dihydro-1′-imidazol-2-ylmethyl) hydrochloride hydrochloride

MsNH

(Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, where Ms = CH3S02 is similar to the above used to prepare N- [3-Ga-5- (4,5-dihydro- 1H-imidazol-2-ylmethyl) -2-methyl-phenyl] methanesulfonamide, but using copper (II) bromide instead of copper (II) chloride to prepare N- [3- Bromo · 5- (4,5-dihydro-1H-imidazol-2-ylmethyl) -2-methyl-phenyl] sulfonamide (melting point 262.4-262.8 ° C). Example 6 Preparation of N- 丨 3- (imidazolidin-2-ylamino) -2-methyl-benzyl 1-methanesulfonamide 138- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 (Mm) 517049 A7 B7 V. Description of the invention (136)

N

Ν- [3 «· (Shenmi Jundian-2-ylamino) -2-methyl-phenyl] pyroxypyramine—-K2-methyl-3-nitro · phenyl) · formaldehyde Amine and n- (3-amino i-benzyl V mesylate ch3

Or SnCl2 / EtOH

H2 / EtOH CH3S02

批 · Batch-(Please read the precautions on the back before filling out this page) Store 2-methyl-3-nitro-aniline (3 g) and methanesulfonyl chloride (1.6 ml) in Pyodo (30 liters, purchased from Mallinckrodt) and stirred at room temperature overnight. Edian was removed under reduced wishes. The residue was taken up in Mallinckrodt and washed with water and brine. After drying over magnesium sulfate and evaporation of each agent ', &gt; j- (2-methyl_3-nitro-phenyl) methanamine (4 g) was obtained. Store N- (2-methyl-3-nitro-phenyl) methanamine (1 · 5 g) and vaporized tin (II) dihydrate (7.4 g) in ethanol (15 ml ) And ethyl acetate (15 liters, purchased from Burdick and Jackson, Muskegon, MI), at the main temperature: 掉 伙. The reaction mixture was treated with a saturated solution of sodium bicarbonate to pH> 9. The mixture was filtered, and the filtrate was washed with water and brine. After drying over sodium sulfate and evaporating the solvent, amine-2-methyl- -139- is obtained. The paper size is in accordance with China National Standard (CNS) A4 (210X297 mm)

1, 1T Member of the Central Standards Bureau of the Ministry of Economic Affairs X Consumer Cooperatives ^ 517049 A7 ------ B7 V. Description of the invention (137) Phenyl) methanesulfonamide (1 g). -~ (Preparation of 2-methylpyridin-2-yldisulfide_2 ^ methyl-phenyl 1methanesulfonamide

The production of di-CH3 by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs was prepared as follows: 2 • imidazoline sulfate (0.5 g, from 2-imidazoline thione and chlorine) according to Tani et al. (Prepared by the procedure reported in She L (1974) 11: 257) was treated with a 1N NaOH solution (10 liters). The 2-gas_2_imidazoline solution was quickly extracted with CHAh, dried over κΑ 03, and filtered to contain N- (3-amino-2-methyl- Phenyl) formamidine (0.3 g, from above) in a flask. The mixture was concentrated in the air to a volume of about 5-6 ml and diluted with isopropanol (about 1 (2 ml)). The mixture was then heated at reflux for 4 hours and the solvent was evaporated. The residue was placed on a stone gel Chromatography was performed with ethyl acetate: methanol: isopropylamine (85: 10: 5) to isolate the desired product (0.2 g) and recrystallize it from methanol to obtain pure ν_ [3_ ( Bite-2ylamino group) -2-methyl-methyl phenyl] formic acid amine, dazzling point 243_244. ^. Example 6A Borrowing of methamidylamine (Please read the precautions on the back before filling in this Page) J ·, item 4 pack, 1T -140- 517049 Λ7 V. Description of the invention (138) A method similar to that described in Example 6, Part 1 was used 'nitronitroaniline as starting material to prepare Ν · (3 · Nitro-phenylmethanesulfonamide and N- (5-amino_2 · methyl · phenyl) -methylpyrazine. 2. N- 『3- (endimidazol-2- Preparation of a certain amino phenyl group] methyl dimethanamine Γ &quot; '^ r, in a manner similar to that described in Example 6, Part 2, using the N- (5-amino-2-methyl -Phenyl) -methanesulfonamide, and N- [3- ( Oxazol-2-ylamino) - phenyl] methanesulfonamide Amides (R34, r35 and r36 = H), m.p. 229.1_22 Shu .6〇C.

Example 6B Preparation of N45- (imidazolidine-2-cetaminyl V2-methyl-ammonium sulfonamide 1 · N- (2-methyl-5 · nitro-phenyl) -methanesulfonate Preparation of Nang and N45-amino-2-methyl-benzylmethanesulfonamide In a manner similar to that described in Example 6, Part 1, using 2-methyl-5-nitroaniline as a starting material, N- (2 · methyl-5-nitro-phenyl) -methanesulfonamide and N- (5-amino-2-methyl-phenyl) -methanesulfonamide are prepared. 2. N -[5- (Hydroxyimidazol-2 · aminoaminophenyl] Preparation of formamidine_ 脍 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -------- # 装-(Please read the back first (Notes on this page, please fill in this page) d In a similar manner to that described in Example 6, except that the starting material is the N- (5-amino-2-methyl-phenyl) -methanesulfonamide obtained above, The N · [5- (endimidazol-2-ylamino) -2-methyl-phenyl] methanesulfonamide (R34, R35 = CH3, R36 = fluorene) was prepared, and the melting point was 123.8-125.5 ° C.

Example 6C Preparation of N-丨 2_Gas-5- (Xinwei Jundian-2-Toluidine) -Dongji] Methylamine-141- This paper is in accordance with China National Standard (CNS) A4 specification ( 210X297 mm) '~~' One 517049 A7 B7 V. Description of the invention (140)

No.2 Na2S2〇4 / CH3〇H / H2〇

R6 = CH3, Cl, or Br

Member of the Central Standards Bureau of the Ministry of Economic Affairs_χConsumer Cooperative Co., Ltd. $! CH3SO2 SnCb / EtOH Example L Part 2 R6 L_Third-butoxycarbonyl-3.5-dinitro-4-methylaniline will contain 3,5- A mixture of dinitro-p-phosphonic acid (20 g), diphenylphosphonium azide (29.2 g) and triethylamine (107 g, purchased from Mallinckrodt) in tert-butanol, in Heat under reflux for 1 hour under nitrogen. The solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (300 mL) and in HC1 (300 mL). The ethyl acetate solution was extracted with a half-saturated sodium vaporized solution, a 1N sodium hydroxide solution (300 ml), and dried over magnesium sulfate. The solvent was evaporated, and the residue was chromatographed on a silica gel, eluting with ethyl acetate: hexane (1: 9) to obtain a small third-butoxycarbonyl_3,5_ dinitrate. 4-Amidinoaniline (7.8 g). ^ Invitation to Dinitrobenzylamine (Please read the notes on the back before filling this page)

^ Clothing II • 143- printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517049 kl B7 V. Description of the invention (141) Will contain N_third · butoxycarbonyl-3,5_dinitro_4, methylaniline A mixture of (7.8 g, from above) and trifluoroacetic acid (100 ml) was stirred at room temperature for 15 minutes. After the solvent was evaporated under reduced pressure, the residue was taken up in ethyl acetate (100 ml), washed with a saturated sodium carbonate solution, a half-saturated sodium chloride solution, and dried over magnesium sulfate. After the solvent was evaporated, the residue was purified by silica gel column chromatography using ethyl acetate: hexane (1: 3) as the eluent to obtain 4-methyl_3,5_di Nitrobenzylamine (2.45 g). 3. Preparation of 5-Gas-2-methyl-1,3-dinitro · benzene 4-methyl-3,5-dinitroaniline (2.1 g, obtained from above) in portions for 5 minutes, Add to a mixture containing a third T nitrite (1.65 g) and copper chloride (π) (172 g) in acetonitrile (40 l, purchased from Malliilckrodt). The mixture was heated at 65 ° C for 10 minutes. The mixture was partitioned between 6N HC1 (200 ml) and ether (200 ml, purchased from Mallinckrodt). The ether layer was separated and washed with 6N HC1 (200 mL) and brine. After being dried over osmium sulfate, and the solvent was evaporated, the residue was purified by flash column chromatography on a lithotripsy gel and lysed with ethyl acetate: hexane (5:95) to isolate 5 -Gas-2-methyl-1,3-dinitro-benzene (2.2 g). t 5-Gas_2_methyl · 3-nitro-benzylamine Preparation of 5-Gas-2-methyl-1,3-dinitro-benzene (1.96 g, from above) under ^, Suspend in methanol (80 mL) and water (20 mL). Sodium dithionite (5.51 g) was added in portions, and the mixture was stirred for 3 hours under a chamber. The reaction mixture was purged and washed with methanol. The filtrate was then removed under reduced pressure, and the residue was partitioned between ethyl acetate (150 ml) and brine (150 ml). The organic layer was dried over magnesium sulfate and evaporated to obtain 5_ -144- I paper size, suitable financial standards (CNS) A Sight (21Gx & ^ 97 mm) '--------- · Equipment-(Please read the precautions on the back before filling this page) Order 517049 A7 B7 ΛΑΟ V. Description of the invention () Gas-2-methyl-3-nitro-aniline (1.45 g). 5. The preparation of N45-qi-3- (benzimidazol-2-ylamino group V2 · methyl-phenyl-1methanesulfonamide is similar to the method described in Example 6, except that the starting material is obtained from the above. 5-Ga-2-methyl-3-nitro-aniline, and N- [5-Ga-3- (endimazolidin_2_ylamino) -2 · methyl-phenyl] methyl continued Fermented amine (R34 = CH3, R35 = hydrazone, R36 = Cl), melting point 230.5-233 ° C.

Example 6E Preparation of N- 丨 5-bromo-3- (benzimidazol-2-ylamino group V2-methyl-moscarpine) mesysulfame 1. 5-bromo-2-methyl grave 1,3 -Dinitro-benzene Preparation (Please read the notes on the back ▲ before filling and filling-: write this page)

, 11 Printed at 80 ° C by the Consumer Cooperative of the Central Bureau of Standards of Didi Ministry at 2-methyl-1,3-dinitrobenzene (10 g) and 1: 1 concentrated sulfuric acid-water (100 ml) ), Potassium bromate (ι0.1 g) was added over 2-2 1/2 hours. The mixture was stirred for an additional 2 hours at 80 ° C and cooled to room temperature. The mixture was poured into 500 g of ice 'and then extracted with ether (300 ml). The ether layer was washed with 10% sodium bicarbonate solution (250 liters) and brine, and dried over magnesium sulfate. After the solvent was evaporated, the residue was purified by flash column chromatography on a silica gel, eluting with ethyl acetate: hexane (4:96), and 5-bromo-2-methyl was isolated. -1,3-dinitro-benzene (5.3 g). _5-Bromo-2 -fluorenyl-3-succinyl-benzylamine production -145- ^ Zhang ruler ^ Applicable to China National Standard (CNS) A4 specifications (210X297 mm) ------- 517049 A7 B7 V. Description of the invention (143 This compound was prepared in a similar manner to that described in Example 6D using 5-bromo-2-methyl-1,3-dinitro-benzene (5.3 g) obtained above. ^ Pyridin-2-ylamino group V} methyl-benzylmethylformamide is similar to the method described in Example 6, except that the starting material is 5-bromo-2-methyl-3- Nitro-aniline, and N_ [Hong bromide_3_ (endimidazolidine_2_ylamino) -2-methyl-phenyl] sulfonamide (r34 = CJJ3, r35 = H, r36 = Br) , Melting point 261.8-262.3 ° C.

Example 6F ----- (Please read the precautions on the back before filling out this page) _ 装 · M 二 [3 _ ((金 多多 -2-ylamino) · _2,5-Difluorenyl-Cerium 1 Green Credit

H2SO4 / H2O

CH

tBuONO / DMF

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

EtOH 02N ^^ &quot; ^ N02 65 ° C ch3 ch3 i · N- (2,5-dimethyl-phenyl) -ethyl amine system Carefully add acetic anhydride (9.2 g) to 2,5 -In dimethylaniline (10.0 g). The mixture became hot and crystallized upon cooling to room temperature. The gray material was recrystallized to obtain 12.6 g of the desired product. -~ Κ3,6-dimethyl-pyridine dinitrodiphenyl v acetamide Preparation of nitric acid containing steam (90 ml) is cooled in an ice bath, and N- (2,5- • 10 , 146 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 male sauce) 517049 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _________B7 V. Description of the invention (144) Dimethyl-phenyl) -acetamidamine (11.2 g, from above) was added in portions over 30 minutes. The mixture was stirred for an additional hour under freezing and allowed to warm to room temperature over 30 minutes. The reaction mixture was carefully poured into 900 g of ice. After the ice has melted, the mixture is filtered and the product to be yellow is washed with water. The ridges were dried under stern air at 80 ° C to obtain hydrazine (3,6-dimethyl-2, cardiodinitro-phenyl) -acetamide (15.5 g). g, 3,6-Dimethyl-2,4-dinitro-benzylamine will contain N- (3,6-dimethyl-2,4 · dinitro-phenylacetamide (14.4 G, obtained from above), a mixture of concentrated sulfuric acid (15 ml), water (30 ml) and ethanol (150 ml), heated under reflux for 24 hours. The precipitated product was filtered, washed with a small amount of ethanol and dried To obtain 3,6-dimethyl-2,4-dinitro-benzylamine (10.3 g). 4_ · __ 2,5-dimethyl-1,3_dinitro · benzene Add a solution of 3,6-dimethyl-2,4-dinitro-aniline (10 g, from above) in DMF (50 ml) at 65 ° C over 5-10 minutes. Tertiary butyl nitrate (B: 61101 ^ 0) (7.32 g) was dissolved in a solution of dimethylformamide (0 ^^) (50 ml, purchased from Mallinckrodt). The mixture was placed at 65 ° C. Heat for 15 minutes under reduced pressure and evaporate the solvent under reduced pressure. The residue is partitioned between dichloromethane (300 liters) and a half-saturated sodium gas solution. The methane solution is added with additional half-saturated sodium chloride The solution (300 ml) was extracted and dried over magnesium sulfate. After the solvent was evaporated, the residue was aspirated. It was collected in digas methane (250 ml) and passed through a short column (silica gel). It was eluted with digas methane to obtain 2,5_dimethyl-i, 3-dinitrobenzene (7.75 G). ^ Preparation of methyl-3-nitrate-jasmine_ -147- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) (1) J1, 517049 A7 ___ ___B7 V. Description of the invention (145) ~~ In a manner similar to that described in Example 6D4 above, from 2, Hong dimethyl · M-dinitrobenzene (7.32 g, obtained from (2) Preparation of 2,5-dimethyl_3-nitro_aniline. Preparation of imidazolidin-2-ylchamoyl-phenyl] methanilamine, similar to the method described in Example 6. However, the starting material is 2% dimethyl-3-nitro-aniline obtained from the above, and N_ [3_ (imidazolidine · 2 • ylamino) _2,5 -monomethyl · phenyl is prepared. ] Methylamine (R34 and cjj3, r36 ~, melting point 232.2-233.4 ° (:.

Example 6G Syndrome-2_yl_waste group) Preparation of 2,3-dimethylformyl sulfamidine (Please read the precautions on the back before filling this page} ▼ 装 _

N- [5- (伸 米 峻 淀 _2_ 基 amino group) _2,3 · dimethyl_benzyl] methanesulfonamide, 11 Staff Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs

-148- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517049 A7 _ 一 _ _ B7 V. Description of Invention (146)

In a similar manner to that described in Example 6F, n- (3,4-dimethyl-phenyl) -acetamide, N- (3,4-dimethyl-2,6-dinitro- Phenyl) · acetamide and 1,2-dimethyl-3,5-dinitrobenzene. L ·: The production of _2,3-monomethyl-5-acyl-aniline is based on N2, and 1,2-dimethyl-3,5-dinitrobenzene (2.5 g, as shown in the above flow chart) The preparation is dissolved in glacial acetic acid (25 liters, purchased from Mallinckrodt) and heated to reflux. The heat source was removed and iron (213g) was added in one portion. After the initial vigorous reaction, the mixture was heated under reflux for 10 minutes and then cooled to room temperature. The reaction mixture was filtered through a celite layer and washed with ethyl acetate. The filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, filtered again through a celite layer, and then extracted with a saturated sodium bicarbonate solution and a half-saturated sodium vaporized solution. After drying over magnesium sulfate and evaporation of the solvent, 2,3-dimethyl-5_nitro_aniline (1 41 g) was obtained. ^ ~~ 土 ΙΑΙΙ succinylamino group) _2,3-dimethylmethyl-phenyl 1-methoxamine, similar to the method described in Example 6, except that the starting material is obtained from the above 2 3 (Please read the notes on the back before filling this page)

-149-

517049 A7 B7 V. Description of the invention (147 monomethyl-5-nitro_aniline, and N- [5_ (imidazolidine · 2-ylamino) _2,3-dimethyl-phenyl] methyl Sulfonamide (r34 = η, R35 and r36 = CH3), melting point 253.6-255.2 ° C. Example 6: oxazolide_2_ylamine 棊) _3_Methyl-phenyl 1methyl ^ amine production ^ L5 -Diaminotoluene Preparation

H2, 10% Pd / c H2N \

EtOH I &gt;-

3,5-Dinitrotoluene (2.85 g, 15.6 mmol) (prepared according to the procedure described in Example 6f) and 10% Pd / C (1.65 g, 1.56 mmol) ) The mixture was stored in 50 ml of absolute ethanol and hydrogenated under hydrogen atmosphere for 20 hours. The mixture was filtered (Watman GF / F) and the ethanol was removed under reduced pressure to give an amber oil, which was used immediately in the next step. λι1-N-methanesulfonylamino-3-amino-5-methyl molybdenum i H2Nv ^ ^ nh2 and Η

MeS〇2Cl CH3S02N ^

I ------- • Equipment ------ Order ------ AW (Please read the notes on the back before filling this page) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs , 5-Diaminotoluene (approximately 1.71 g, 1.53 mKear) was dissolved in pyridine (35 ml), and the resulting solution was cooled to. Methylpyrazine (1.53 g, 1.32 mol, Aldrich) was added dropwise, and the mixture was allowed to warm to room temperature. After stirring for 14 hours, the solvent was removed under reduced pressure. The mixture was diluted with brine and extracted with ethyl acetate. Dry the extract (MgS〇4) 150 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 Λ7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (彳 48) and concentrated , To obtain 2.7 grams of orange-red solid. The crude product was previously adsorbed to SiO2i containing methanol and subjected to chromatography (200 g of SiO2, 45% ethyl acetate / hexane) to obtain 0.41 g of the product (Me = CH3). ^ Imidazolidin-2-ylamino) -3-methyl-phenyl 1methanesulfonamide is prepared in a similar manner as described in Example 6, except that the starting material is 1-N · methanesulfonamide · 3-Amino-5 -methylbenzene, and N- [5 "(endimidazol-2-ylamino) -3 · methyl-phenyl] formamic acid amine (R34 = η, R35 = Η, R36 = CH3), melting point 54-77 ° ς. Example 61 (Semimidazo-2 -ylamino) _3_Chloro-phenyl 1 methylphenamine was prepared similarly to that described in Example 6). Method, except that the starting material is% a-pyridine, 3 · phenylenediamine 'to prepare N- [5- (endazolidin-2-ylamino) _3_a-phenyl] methanesulfonium Amine, melting point 232.9_233.7 ° C. Example 6 J (Eximidazol-2-ylamino) -3-methoxy-benzyl phosphonium was prepared by a method similar to that described in Example 6H, except that The starting material was 3 5_dinitromethoxybenzene ′ to prepare N- [5 · (tenamiben-2-ylamino) _3_methoxy-phenyl J methanesulfonamide, melting point 219.3 -219.7 ° C. Example 6K Preparation of N- [3- (endimidazol-2-ylamino) -5-isopropyl 1-methylpyrrolidine The method described in Example 6H was used except 5 • isopropyl- -151 · (please first Read the notes on the back and fill in this page again)-Install ·, 11 d This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 517049 A7 B7 V. Invention Explanation (149) Methyl-1,3-dinitrobenzene, and N- [3- (endimazolidin-2-ylamino) -5-isopropyl-2-methyl · phenyl] was prepared Methylpyrazine, melting point 23 1.8-232.3 ° C. Example 7 Preparation of N- 丨 3- (1Η-imidazol-4-yl_methoxybenzidine 1 methanesulfonamide Ϊ. ΗΓ \ Ν- [ 3- (1Η- 味 峻 -4-ylmethoxy) -phenyl] 曱 amine

丄 · 4- (3-Nitro-phenoxymethyl) -1 · trisylmethyl-1H-Wei Junzhi Preparation of (1-triphenylfluorenyl-1H-imidyl · 4 · yl) -methanol ( 2.23 g, prepared as described in J Med. Chem. (1977); 72 1) was added with 3-nitrophenol (2 g), and diethyl azide dicarboxylate (2.1 ml) was dissolved in tetrahydrofuran (THF) (40ml) -152- This paper size is applicable to China National Standard (CNS) A4 (210X297mm) ----; ------ (Please read the notes on the back before filling in this Page), 1T 517049 A7 _ B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Solution of the Invention (150). A solution of triphenylphosphine (3.44 g) in THF (60 liters) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature overnight. After the solvent was evaporated, the residue was chromatographed on silica green gel with ethyl acetate: hexane (40:60) and separated to obtain 4- (3-nitro-phenoxymethyl) _1-trityl-1H-imid (2 g). The preparation of _2 · 3-Π-trityl-1H-imidazol-4-ylmethylamino) aniline will contain 4- (3-nitro-phenoxymethyl &gt; -1-trityl- A mixture of 1H · imidazole (1.5 g from the above) and 10% Pd / C (0.18 g) in ethyl acetate (60 ml) and ethanol (30 ml) was subjected to hydrogenation at 1 atmosphere overnight. The reaction mixture was filtered through a celite layer, and the filtrate was evaporated under reduced pressure. The residue was passed through a crushed stone gel, and was quenched with ethyl acetate: hexane (40:60) to dissolve the flash tube. Purified by column chromatography to obtain 3- (ι_triphenylshenyl-1H_imidazol-4-ylmethoxy) aniline (0.6 g). 1, _Ν- [3_ί_ί: ϋmethyl-1H · Preparation of imidazolium 4-methyl argon, phenyl 1-methanesulfonamide will contain 3 · (1-trityl-1 hydrazone-imidazol-4-ylmethoxy) aniline (07 g, obtained from The above) mixture with methyl hydrazone gas (0.3-liter) stored in Edian (12 ml) was stirred overnight at room temperature. Edian was removed under reduced pressure. The residue was dissolved in digas methane, It was then washed with water and brine. After drying over magnesium sulfate and evaporation of the solvent, N- [3 · (1-tribenzene -1Η • imidazolylmethoxy) -phenyl] methanesulfonylamine (0.7 g). —-HdU1 technical diweijunylmethylamino group] · phenyl [Methyl green amine preparation will contain N- [ 3- (l-trityl · 1Η-imidazol-4-ylmethoxy) _phenyl] methanesulfonamide (0.63 g 'from the above) and in HC1 (10 liters) in B Bet (10-153- This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 public attack) -ϋ I---...... m 1--11 ......... -j— 丁 I-1 = 1 I-(Please read the precautions on the back before filling this page) 517049 A7 _____________ B7 V. Description of the invention C151) ml) Stir at room temperature overnight. The solvent was removed and the residue was adjusted to basic pH with saturated potassium carbonate solution. The mixture was extracted with dichloromethane, washed with brine and dried over sodium sulfate. After the solvent was evaporated, the residue was chromatographed on a silica gel and eluted with methanol (containing 2% NH4OH) / dichloromethane (7:93) to obtain N- [3- (1Η-imidazole). 4-ylmethoxy) -phenyl] methanesulfonamide. This was converted to N- [3- (1H-imidazol-4-ylmethoxy) -phenyl] methanesulfonamide oxalate by treatment with a 1 M oxalic acid ether solution, melting point 178-180 ° C. Example 8: "2-Methyl 3- (Suzakizolidine-2-ylaminophenyl 1-methanesulfonamide) ------ ^ -------- (Please read the back first Note before filling out this page}

· Consumer Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs, Yinfan N- [2-methyl_3_ (endazolidine_2_ylamino) -phenyl] sulfonamide

4. At 0 ° C, add 2-gas ethyl isocyanate (0.7 ml) dropwise, N &lt; 3-amino · 2-fluorenyl-phenyl) -methanesulfonamide (1.5 g, obtained from the implementation Example 6, part 1) was stored in a mixture of THF (30 ml). Slowly warm the reaction mixture -154- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) 517049 A7 ___ ___B7 V. Description of the invention (152) ^ to room temperature and stir overnight. The precipitate was filtered, washed with THF, and dried to obtain N- {3- [3- (2-chloro-ethylethyl) · 2 · methyl-phenylmethanesulfonamide (18 g). Potassium (40 wt ·% on alumina) (3.5 g) was added to the above compound (1.7 g) in acetonitrile (100 liters). The mixture was heated at 80 ° C for 8 hours and Filter and wash with methanol. Evaporate the filtrate under reduced pressure. Purify the residue by flash column chromatography on silica gel with methanol: dichloromethane (5:95) to obtain N -[2-methyl-3 (Xinyinlingdian_2_ylamino) -phenyl] methylene amine. This was converted to oxalate in a manner similar to that described in Example 7, Section 4. · 5 g), melting point 124 · 14 ×: Example 9 1 Gasification of N, N_dimethyl-N, -Γ3- (4,5-dihydro-1H-imidazylphenyl 1 Amine No. # (Read the precautions on the back before filling in this page)

Hydrogenated N, N-dimethyl-N, _ [3_ (4,5_dihydro-1H-imidazole_2_ylmethoxy) -benzyl] continuous diamine is consumed by staff of the Central Standards Bureau Printed by a cooperative

ch3 —-— methyl-N ’-(3 · Methylmethyllactyl epitope) _Enzyme-neck system -155-

517049 Α7

Tarabu added dimethylamine sulfonium gas (4.2 ml) dropwise over 10 minutes to (3-aminophenoxy) -acetonitrile (1.5 g, obtained from Example 1), triethyl The amine (3.22 ml) was dissolved in a solution of THF (35¾ liters). After stirring at room temperature for j hours, the solvent was evaporated, and the residue was partitioned between methane and water. The organic layer was extracted with a 5% HC1 solution and dried over magnesium sulfate. After the solvent was evaporated, the residue was purified by flash chromatography on silica gel with ethyl acetate: digas methane (10:90) to obtain N, N_dimethyl ^, _ ( 3. Sulfuryl methyl lactyl hydrazine)-horizontal brewed diamine (111 g). -—— I gasification of N, N_di [yl-N, _Γ3 · ί4 · 5-dihydro-1H-protamine-9 ^ The method described starts from N, N-dimethyl-N,-(3-aminomethoxyphenyl) · sulfonamidodiamine to prepare hydrogenated N, N • dimethyl-N '· [3. (4,5_Dihydro-1fluorene-imidazol-2-ylmethoxy) -phenyl] fluorendiamine, melting point 198.5-20TC. Example 10 Preparation of Huangqi N-Methanesulfonyl_6 · (4,5-dihydro_1Η_imidazole-2_ylmethyl) Wobdor (Please read the precautions on the back before filling this page ) Qin,-Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Oral Affairs

SG2Me where Me =: Preparation of CH, v_y N-methanesulfonyl-6-carbonylmethoxyindole 156 The paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 517049 A7 _______B7 V. Description of the invention (154)

At -78 ° C, a solution of NaN (TMS) 2 (lM) in THF (11 mmol, U 亳 L) was added dropwise to 6-carbonylmethoxyoxindole (876 mg, 5 mmol) Moore, prepared according to the method of Batcho et al., Q-rg · Svnth · Col · 7: 34 Lu Jinshu) was dissolved in a solution of dry THF (10 ml). After stirring for 30 minutes, MeSO2Cl (1.47 ml) (Me = CH3) was added. The mixture was allowed to stir overnight and then poured onto 100 ml of water. The mixture was extracted with CH2C12 (2 X 75 mL). The extract was washed with brine, dried (Na2SO4), and the solvent was removed by a rotary evaporator to give a light brown solid. The solid was purified by flash chromatography (silica gel, 20% ethyl acetate / hexane) to obtain 510 mg of N-methanesulfonyl-6-carbonylmethoxyindole. 2 · Preparation of N-methanesulfonyl-6-hydroxymethylcarboxole

Where Me = CH3 (Please read the notes on the back before filling this page) _ 装 _

1, 1T printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (under 'TC'), a solution of hydrogenated Ming | I (1M) in THF (2.57 millimoles, 2.57 ml) was added dropwise to N-formyl -6-Carboxymethoxy, obtained from the above, was dissolved in a solution of dry THF (10 ml). After 30 minutes, 0.5 ml of water was added dropwise, followed by 0.5 亳 · μμ NaOH solution was added. Diatomaceous earth was added and the mixture was filtered through a coarse-grained funnel. The solid-157- this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 517049 rO ^ OH S〇2Mg fXX ^ Br S〇2Me A7 B7 V. Description of the invention (155) The body was washed with 20 ml of ethyl acetate. The filtrate was concentrated under vacuum. The product was subjected to flash column chromatography (silica gel, and the column was filled with toluene). , Gradient elution 20-50% ethyl acetate g / §) and purification, to obtain 370 g of N-formamidine hydroxymethyl indole, a white solid (yield 80%). Preparation of a 6-bromomethyl bow! Indole

CBr4, Ph3p CH2C12, 0 ° C

Br where Me = CH3 will be N-methylidenyl-6-hydroxymethylxanthene (34 mg, i 51 mmol, obtained from above) and diphenylphosphine (PhP) (4 5 mg, l • 58 mmol of solution in 5 ml of THF was cooled to 0 ° C, and a solution of carbon tetrabromide (551 mg, i% mmol) in 3 ml of dry CHAh was passed through a catheter (2 ml of CHaCh (Washing) add dropwise. The reaction mixture was allowed to warm to room temperature. After 4 hours, the solvent was removed by a rotary evaporator and the resulting purple oil was purified by flash column chromatography (silica gel, 2000/0 ethyl acetate / hexane). Thus, 290 mg of N.methanesulfonyl-6-bromomethylcarboxole was obtained, which was a colorless oil which solidified upon standing (yield 67/0). i: Production and storage of a base-6-cyanomethyl benzoin ^ Binding (read the precautions on the back before filling this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Dioxane / H20

NaCN

S〇2Me 〇Ν Where Me = CH3 N-formyl-6-bromomethylindole (280 mg, 097 millimoles, S〇2Me get 158- this paper standard universal 'National Winter Standard ( CNS) A4 specification (21Gx297 public manager 517049 A7 B7 V. Description of the invention (156) from above) Dissolved in 1 ml of diazane. Water (1 liter) was added, followed by NaCN (52 mg, 1.07 mmol) ) Added. The mixture was stirred at room temperature for 9 days. The reaction mixture was diluted with 30 ml of ethyl acetate and washed with water. The aqueous layer was washed with 30 ml of ethyl acetate. The combined extracts It was extracted with brine, dried (NajO4), and concentrated. The crude product was purified by flash column chromatography (silica gel, 40% ethyl acetate / hexane) to obtain 216 g of the desired N -Methanesulfonyl-6-cyanomethoxyindole (yield 95%).-· Helium Qinization 6- (N. Read the notes on the back and fill out this page)

SOgMe

HCl, EtOH

, 1T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Where Me = CH3. N-formamidine-6-cyanomethylbutorol (192 mg, 0.82 mol, obtained from above) was dissolved in 5 ml of dry CH2C12 solution containing 0.24 ml of absolute ethanol. ' Treat with HC1 for 1 minute. The reaction flask was capped and the mixture was allowed to warm to room temperature. After stirring for 36 hours, all volatiles were removed to give a foamy white solid which was used without purification. ^ Hydrolyzed N-methylsulfonyl-6- (4,5-dihydro-1H-imidazole-2-one methyl 1 5L

-159 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X 297 mm) 517049 A7 _________ B7 V. Description of the invention (157) Where Me = CH3 will be ethylenediamine (82 microliters, L23 millimoles) Add to a solution of 6- (n-methanesulfonamidoindolyl) -acetamidate (0.26 g, from above) dissolved in 5 ml of dry methanol. The mixture was stirred at room temperature for 18 hours. Crushed stone gel (5 g) was added and the mixture was dried by a rotary evaporator. The resulting powder was sampled into a crushed stone gel column, and was dissolved in an 85: 10: 5 mixture of ethyl acetate: methanol: isopropylamine to obtain 161 mg of N-methylsulfonyl-6- (4 , 5-dihydro-1H-imidazol-2-ylmethyl) &lt; indole. The product was dissolved in 5 ml of HCl (1.0 M) in diethyl ether. The solvent was removed by a rotary evaporator. The product was cooled to -4 ° C, and the resulting crystals were washed with acetone. After drying, 210 ¾ g of lice N-formyl chloride-6- (4,5 -dihydro-1H -taste smell 2 Methyl group). Example 11 Refluorinated N-methanesulfonyl dong (an imidazolidine-2-ylamine, tablet 丨 (Please read the precautions on the back before filling this page)-Order

Where Me = CH3 N-Methenyl-6-nitropyrene M g. 4. Prepared by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Distillation ^

NaN (TMS) 2,

MeS〇2Cl, THF, -78 ° C ° 2N where Me = CHi XX) S〇2 ^ 0 -160- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 517049 A7 _____ B7 V. Invention Explanation (158) At -78 ° C, a solution of NaN (TMS) 2 in THF (12 ml, 12 mol) was added to 6-nitrooxindole (1.62 g, 10.0 mmol) Ear) dissolved in dry THF solution. MeS02Cl (1.37 g, 12.0 mol) was added after 20 minutes. The reaction mixture was warmed to room temperature and filtered after 1 hour. The solid was boiled with aqueous methanol (30 liters) and then filtered again. After being dried to a constant weight in the air, 2.07 g of product was obtained (yield 86%). Preparation of 2 · N-formamyl-6-amino group

Store a mixture of N-methanesulfonyl-6-nitroindole (2.52 g, 0.82 mmol, from above) and oxidized sodium (119¾ g '0.52 mmol) in 100 ml of methanol. Hydrogenation was performed in a Parr unit for approximately 1 hour until a constant pressure was obtained (initial 42 psi HO. The catalyst was removed by filtration (Watman gF / F) 'and the filtrate was concentrated by a rotary evaporator to obtain N-formaldehyde. Sulfonyl-6-aminopyridine, which is oily, solidifies when it is left to stand in an argon atmosphere. (Please read the precautions on the back before filling out this page} I Install · Book-# · Staff of Central Bureau of Standards, Ministry of Economic Affairs Consumer Cooperative Press F 5.1_ Preparation of Hydrogenated N-Methylidene-6- (Shenmi Jundian-2-ylamino)

Where Me = CH3 -161-This paper size is applicable to Chinese National Standard (CNS) A4 specification (21〇X: 297 mm) 517049 A7 B7 159 V. Description of invention ((Please read the precautions on the back before filling this page) 3.82 g of 2-imidazoline hydrogen sulfate (see Example 6A) was treated with 50 ml of a 1M NaOH solution and immediately extracted with CH 2 Cl 2 (3 × 20 μL). The extract was dried (K 2 CO 3), and The solution was decanted lightly. 10 liters of isopropanol was added, and CHaCh was removed under reduced pressure. The resulting isopropanol solution was added to the solution, and N · methanesulfonyl-6-aminoindene was contained in the reflux. Indole (202 g, 9 61 mmol) was dissolved in a solution of isopropanol (10 liters). The mixture was refluxed for 3 hours, cooled, and concentrated under vacuum. A portion (800 mg) of the crude product Soluble in MeOH: Η20 (5 ·· 1), and then add 10 g of silica gel. Dry the mixture in air and apply the resulting powder to a silica gel column, and use ethyl acetate. Esters: MeOH · iPrNH2 (93: 5: 3) (ipr = isopropyl eluate. The obtained white solid was suspended in MeOH (4 ml) and 3 * 1.0 乂 HC1 / ether treatment. The solid was dissolved first, and then the mixture was cooled in an ice bath to form a precipitate. 590 mg of hydrogenated N-methanesulfonyl group · 6 · (benzimidazol-2-ylamino group) was obtained. p5 indole (melting point i67 6-17).

Example 11A I gasification of 6- (endylamino) indolyl dimethylsulfonate

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economics of China S2NMe2 where Me = CH3 is similar to the method described in Example 11, except that N, N-dimethylamine sulfonium gas is used instead of methyl chloride. , And 6- (indimidazol-2-ylamino) pyridine | indole-1-sulfonic acid dimethylamidine (melting point 192.4-193.0X :) was prepared from 6-nitroindole (Lane aster). -162- This paper size is in accordance with Chinese National Standard (CNS) 8 4 specifications (21 × 297 mm) 517049 A7 B7 V. Description of the invention (160 Example 11B imimidazol-2-ylamino group 1- (propyl Preparation of -1-sulfofluorenyl V1H-indole-6-yl μamine Λ

So2n-Pr 4 was prepared from 6-nitrocarboxole (Lancaster) in a manner similar to that described in Example 11, except that methanesulfonium was replaced by methanesulfonium. Imidazolidine-2 · ylamino- [1- (prop-1-sulfonyl) -1Η-pyridin-6-yl J-amine (melting point 212 · 6-213 · Γ (:). Example 11C 6 · (4,5_Difluoren-1H · imidazol-2-ylmethoxy) -1 · Methanesulfonyl-1H · pyridine

-ΝΗ Ms where Ms = CH3S02 1-methanesulfonyl-1H · pyridin-6-ol ------------- IT ------ ml (Please read the back first Please fill in this page before printing) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 1. H2S〇4, NaN02-&gt; &gt;-2. C11SO4, H2O, return Ms Ms where Ms = CH3S02 will be like Buddha Forbes et al., J. Med. Chem. Π996) 39: 4968, the N-methanesulfonyl-6-aminochordole (2.10 g, 10.0 mmol) was suspended in 10 ml of water , And then cooled in an ice bath. Concentrated sulfuric acid

163- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 517049 Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (161) (3 liters) slowly added dropwise. The mixture was warmed to room temperature for 5 minutes and then cooled to OT: again. A solution of NaN02 (Mallinckrodt, 0.76 g, 11.0 mmol) in 10 ml of water was slowly added, and the resulting foam was treated with 10 l of ethanol. The mixture was added in portions to a boiling solution of CuSO4 (J.T. Baker, 16.0 g, 0.1 mole) in 75 ml of water. After 15 minutes, the mixture was cooled. The formed brown solid was broken up with a stirring rod. NaHC03 was added to neutralize the reaction, and the product was extracted with ethyl acetate (2 × 100 ml). The extract was dried (anhydrous MgS04) and concentrated to give 1-methanesulfonyl-1H-indole-6-ol (1.62 g) as a brown oil which was used without purification. Preparation of (1-Methanesulfonyl-1H-pyridin-6-yloxy) acetonitrile

Ms Ms where Ms = CH3S02 dissolve 1-methanesulfonyl · 15-, 5 · indol-6 · ol (1.62 g, 7.7 mmol) in 10 ml of methyl ethyl ketone. Cs2C03 (Aidrich, 7.5 g, 23.0 mmol) was added, followed by bromoacetonitrile (1.85 g, 15.4 mmol). The mixture was allowed to stir overnight. The mixture was diluted with water, and the product was extracted with ethyl acetate. The extract was washed with brine, then dried (anhydrous MgS04), and concentrated by a rotary evaporator. (1-Methanesulfonyl-1H-indole-6-yloxy) acetonitrile was purified by chromatography (SiO 2, eluted with 30% ethyl acetate / hexane). 780 mg (yield 37% from 1-methanesulfonyl-1-fluorene-6-ol). —- 6- (4 · 5_diazepine-1Η · Wijun-2 -ylmethoxy) -1-methyl ceryl _ 1Η- -164 This paper size applies to China National Standard (CNS) A4 (210X297) Mm) -------- mr installed ------ order ------ (Please read the precautions on the back before filling this page)

NCT

BrCHsCN, CS2C03 ---- ^ MEK 517049 Α7 _ Β7 V. Description of the invention (163) 1 · 3-Bromo-6-nitro ...

The fraction of N-bromosuccinimide (2.31 g, 12.95 mmol) was added over 5 minutes, and 6-nitroindole (Lancaster, 2.0 g, 12.33 mmol) was dissolved in 12 ml of dry Cl ^ Ch Of solution. After 18 hours, the solvent was removed and the solid was chromatographed (200 g of SiO2, eluted with 2: 1 hexane / ethyl acetate) to give 2.62 g of 3-bromo-6-nitrofluorene Indole (88% yield). Preparation of 2 · 1-methanesulfonyl-3-bromo-6-nitropyridine

Br

Printed by the Consumers' Cooperative of the Central Bureau of Standards of China. 3-Bromo-6-nitrobutyro (1.50 g, 6.22 mmol) was dissolved in 10 ml of a solution of THF. The solution was cooled to -78 ° C. NaN (TMS) 2 (7: ml, 7.5 mmol, 1.0 M in THF) was added dropwise to produce a dark red solution. Dimethan (0.71 g, 6.22 mmol) was added dropwise to make the release red disappear. The reaction was warmed to room temperature. After 2 hours, the mixture was poured into water and extracted with ethyl acetate. The extract was dried (anhydrous MgS04 and concentrated. The resulting solid was boiled with 5 ml of acetone, and then the acetone beta dropper was aspirated to obtain 1.55 g of the product (yield 78%). 3 · 1- Formamidine _3_ Mo_6 · Preparation of amine Θ Budor 166 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 meal) 517049 A7 B7 V. Description of the invention (165) Hydrochloric acid Preparation of imidazol-2-yl-II-methanesulfonyl-3 · methylmole-6-ylamine

Where Ms = CH3S02 Preparation of N- (2-bromo-5-nitrophenyl) methanesulfonamide

1. MeSOaCI, pyrCH2Cl2, 0 ° C 〇2ΐΓ ^^ ΝΗ2 2. aq. NaOH, MeOH 02hrv ^^ NHS02Me where Ms = CH3S02 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ----------- (Please Read the precautions on the back before filling this page), 11 at 0 ° C, add methanesulfonyl chloride (1.26 g, 18.43 mmol) to 4-nitro-2-aminobromobenzene (1.6 g , 7.37 mmoles) and triethylamine (1.86 g, 18.43 mmoles) were dissolved in 20 ml of a solution of CH2C12. The reaction mixture was warmed to room temperature and stirred for 72 hours. The mixture was poured onto 50 ml of 1M HC1 and extracted with 2 × 100 ml of ethyl acetate. The extract was washed with brine, then dried (anhydrous MgS04), and concentrated. The material was dissolved in 10 ml of methanol and treated with 10 ml of a 3M NaOH solution. The mixture was stirred overnight. The methanol was removed under reduced pressure, 10 ml of water was added, and the solution was extracted with 50 ml of CHAb. The aqueous layer was acidified to pH 1 by adding concentrated HC1 dropwise. The product was extracted with ethyl acetate (2 X 75 mL). The extract was dried (anhydrous MgS04) and concentrated to give 2.46 g of N- (2-bromo-5-nitrobenzyl) formamic acid amine. —- Health., Preparation and storage of stilbyl-N- (2-bromo-5-nitrophenyl) formamidine -168 · 517049 A7 B7 V. Description of the invention (166

Br

Cs2C03, MEK NHS02Me

Br

Add allyl bromide (1.36 g, 11.25 mmol) to n- (2h acylphenyl) methanesulfonamide (1.66 g, 5.62 mmol) and carbonic acid (549 g, 16.86 mmol) ) In a mixture of methyl ethyl ketone (20 ml). The mixture was heated to reflux for 2 hours. The mixture was cooled and poured onto water. The product was extracted into ethyl acetate (2 × 75 ml), and the extract was dried (anhydrous MgS04), and concentrated to obtain 88 g of N-propylpropyl-N- (2. Phenyl) Methylamine, which does not need to be purified. 1-Methanesulfonyl · 3-methyl-6-nitro-1Η-pyridoxine n (Read the precautions on the back before filling out this page) 装 装 · NS02Me

Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. According to the method of Martin, Helv. Chem. Acta (1989) 721554, N-fluorenyl-N- (2-bromo-5-nitrophenyl) formamidine (2 μg, 7.31 mmol), palladium acetate (83 mg, 0.37 mmol), tri-o-tolylphosphine (222 g, 0.73 mmol) and diisopropylethylamine (42 g, 11.0 mmol) Mol) in a mixture of 10 ml of toluene and heated to reflux for 18 hours. The reaction was cooled and teared through a fine Wattman glass fiber filter to remove palladium. The mixture was diluted with 100 ml of ethyl acetate, and then sequentially washed with 1 M HC1 (50 ml) and brine. Dry the extract (anhydrous 169 paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 517〇49 Central Consumer Bureau of the Ministry of Economic Affairs Staff Consumer Cooperative Cooperative Printing f

A7 B7 V. Description of the Invention (167)

MgS04) and concentrated. The crude product was dissolved in acetone. Silica gel (10 g) was then added and the solvent was removed under reduced pressure. The resulting powder was applied to a crushed stone gel column (110 g), and was eluted with 25% ethyl acetate / hexane to transfer 1.17 g of 1 · methylpentyl-3-methyl-6- Nitro-1Η · ν5 丨 Voice (yield 63%). Preparation of 1_Methanesulfonyl-3-methyl-6-amino-1A-pyridine

Store 1 · methanesulfonyl-3-methyl-6-nitro-l / ί-indole (1.17 g, 4.60 mmol) and platinum oxide (52 mg, 0.23 mmol) in A mixture of 20 ml of absolute ethanol was hydrogenated under hydrogen pressure at room temperature for 12 hours. The mixture was filtered through a fine Wattman glass fiber filter to remove the catalyst. After the ethanol was removed under reduced pressure, a quantitative amount of i • methanesulfonyl-3_methyl_6 • amino group was obtained. ^ —— 1AiMt imidazolidin-2-yl- (1-methylsulfonyl-3-methyl-ih-H 丨 indol-6-yl) -amine

iPrOH, 82 ° C where Ms = CH3SO2 by a procedure similar to the preparation of hydrogenated N_methanesulfonylimidazolidine_2_ylamino group) &lt; indole, from sulfonylsulfonyl_3_methyl ^ amine Hydroxylimidazol-2-yl- (1-methanesulfonyl_3-methyl-1H sulfonium) prepared by the radical _1H ^ indole 丨 -170- This paper size is applicable to the Chinese country ^ TcNS) A4 size (210X297 (Mm) '(Read the precautions on the back before filling this page)

517049 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs This composition contains: Active ingredients Lactose Magnesium stearate kl ____ 5. Description of the invention (168) Indole-6-yl) -amine (melting point 236.4-236.7 ° C).

Example 11F Bichloroimidazolidin-2-yl- (1-methanesulfonyl-3- 氪-丨 Hou_6 • Preparation of an amine similar to that described in Example 11D for the preparation of hydrochloride Wei 4 bite _2_yl- (1-methylpyridinyl-3-bromide-6-yl) · amine method, but starting from &amp; air succinimide instead of N-bromosuccinimide, Preparation of hydrochlorinated oxazosin_2_yl- (1-methanesulfonyl-3-gas-1H-indole-6-fluorene) _amine (melting point 232.5-234.0 ° C)-

Example 11G Hydrogenation of Junweijido 2-yl- (1-methylsuccinyl-3-cyano-1K-H-6. The preparation of amines was similar to that described in Example 11D for the preparation of hydrogenated elongation. The method of imidazol-2-yl- (1-methanesulfonyl-3-bromo-1H · indole-6-yl) -amine, starting with chlorosulfonyl isocyanate instead of N-bromosuccinimide According to the process of synthesis (1978) 374 by Mehta et al., Hydrogenated imidazolidinyl- (1-methylsulfonyl-3-cyano-1H-pyridin-6-yl) -amine was prepared. (Melting point 199-199.5. (:). Example 12 Composition for oral administration% wt./wt. 20% 79.5% 0.5% -171 · ^^ Applicable to China National Standard (CNS) A4 specification (210X297 mm) ) (Please read the notes on the back before filling out this page)-Packing _ 517049 A7 ___ B7_____ V. Description of the invention (169) Mix the two groups of ingredients and disperse them into capsules containing 100 g each; one capsule will be approximately equal to Total daily dose. Example 13

I Composition for oral administration (please read the precautions on the reverse side before filling out this page) I pack this composition ..% wt./wt. Active Ingredient 20.0% Magnesium Stearate 0.5% Crosslinked Rebel Sodium cellulose 2.0% lactose 76.5% PVP (polyethylene pyrrolidine) 1.0% The above ingredients are combined and granulated using methanol as a solvent. The formulation is then dried and formed into tablets (containing 20 mg of active compound) using a suitable tableting machine. Example 14 The composition contains: the active ingredient sodium vaporized water for injection is added to d parenteral limulus blend (IV1% Wt./wt. 0.25 g) 100 ml of isotonic solution dissolves the active ingredient in a portion of water for injection. Then, a sufficient amount of sodium carbonate is added with stirring to make the solution isotonic. The solution is added to the desired weight with the remaining water for injection and passed through a 0.2 micron membrane filter Filtration and packaging under sterilizing conditions. Examples 15 -172 · The paper size is suitable for household use (CNS) A4 specifications (210X297 male 517049 A7 B7 V. Description of the invention (17〇) suppository I biocomplex% wt ./wt. 1.0% 74.5% The composition contains the active ingredient polyethylene glycol 1000 polyethylene glycol 4000 24.5% The ingredients are melted together and mixed on a steam bath, and poured into a total weight of 2.5 grams Example 1 6 Composition of local preparations in grams. Active compound 0.2-2 Span 60 2 Tween 60 2 Mineral oil 5 Petroleum 10 methyl paraben 0.15 propyl paraben 0.05 BHA (Butylated hydroxymethyl Oxybenzene) Add 0.01 water to 100 · Appropriate! (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, combining all the above ingredients (except water) and heating with stirring To 60 ° C. Then add a sufficient amount of water with vigorous stirring at 60 ° C to emulsify the components, and then add water to a sufficient amount of 100 grams. Example 17 Nasal Spray Blend 173- present Paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Distillation 517049 Α7 B7 V. Description of the invention (171) Several aqueous suspensions containing 0.025-0.5% active compounds The liquid preparation is a nasal spray spray blend. These blends contain inactive components, such as microcrystalline cellulose, sodium carboxymethyl cellulose, dextrose, etc. as needed. Hydrochloric acid can be added to adjust the pH. Nasal spray blends can be delivered via a nasal spray metering pump, typically delivering 50-100 microliters of the blend at each activation. A typical dose is expected to be 2.4 every 4-12 hours Spray time Example 18 gAlA / lL • Adrenaline receptor activity fraction i / f Unless otherwise specified, the compound used in this Example 18 was purchased from sigma chemical company, St. Louis, MO, USA) A. In vitro analysis will be Male white New Zealand rabbits (3-3.5 kg) and 8? ^-Like-oamp; \ ¥ 16 乂 rats (250-400 g) were suffocated with CO2 asphyxiation. Remove the bladder (rabbit) or aorta (rat), remove the extra-organ tissue, and place the tissue in oxygenated Kreb's solution (mM: NaCl, 118.5; NaHC03, 25; dextrose, 5 Kα, 4.8; CaCl2, 2.5; MgS04, 1.2, &amp; K2P04, 1.2). Cocaine (30 μM), corticosterone (30 μM), ascorbic acid (100 μM), indomethacin (10 μM), and dioxan (1 μM) were added to the Kreb, s solution, respectively. Blocks neuronal absorption, external nerve absorption, auto-oxidation of catechin, prostanoid synthesis, and beta-adrenergic receptors. Avar 2. adrenoceptor antagonist idazoxan (0.3 μM, Graduate Chemical Company, Netizek, MA, USA ·) and calcium nitrate antagonist nitrosethyl methyl ester (10 μM, international Postgraduate company, Netick, MA, 11.8.8.) Were added to the Kirschnerfeldt (German 1) and} solution for rabbit hands and atmospheric experiments, respectively. -174- This paper size applies to China National Standard (CNS) Α4 specifications. (210 × 297 mm) ---------- (Read the precautions on the back before filling in this page), 1 '517049 A7 Printed by the employee consumer cooperative of the Central Standards Bureau of Didi __ B7 V. Invention Description (172). A thin strip of bladder neck (rabbit) approximately 0.8-1.2 cm in length and 24 mm wide and an aortic ring (2-4 per rat) approximately 3 mm wide (close to the heart as close as possible) are placed at a resting tension of 1 Next, suspended in a water-coated tissue bath. The tissue was maintained at 34 ° C with continuous oxygen / carbon dioxide mixture. The tissue was contacted with norepinephrine (10 μM) and washed for 60 minutes before establishing the first cumulative concentration-effect of norepinephrine. The tissue was then washed for 60 minutes before establishing a second cumulative concentration-effect on the test activator. The concentration (pec50) and actual activity (relative to norepinephrine) of the half-maximum tadpole response were recorded. Results of measurement of standards and representative compounds of the present invention. In this analysis, representative compounds of the present invention showed activity. B. In vivo analysis: Anesthetized pig urethra / blood pressure pattern: Female Yucatan mini pigs (12-35 kg; g 10 months old) were treated with ketamine (Aveco, Dodge City, IA, USA), followed by pentobar Anesthesia was performed for Bitot (Schering Plough Animal Health, Kenniwoz, nJ, USA). Place the endotracheal tube of the endless belt into the trachea, and mechanically ventilate the pig with room air under positive pressure. Separate the right and left femoral arteries and veins and insert the cannula. Using one of the cannulas inserted into the femoral vein, pentobarbital (5-20 mg / kg / hr) was introduced by a perfusion pump. Test compounds were administered using a second catheter. A cannula inserted into the femoral artery was connected to a blood pressure transducer (Gould / StathamSprectamedP23 series) to measure arterial blood pressure. The needle electrode was subcutaneously inserted into the recording limb lead ECG, and the heart rate was detected by a flow velocity meter using the R-wave target of the ECG. Body temperature is maintained by Aquamatic hot water-covered bag (κ_20 type), and YSI remote sensing temperature -175 · (read the precautions on the back before filling this page) 4 items to be refilled and packed ·

、 1T This paper size applies Chinese National Standard (CNS) A4 specification (210X297 male sauce) 517049 A7 B7 5. Description of the invention (still) The meter (43TA type) detects anal temperature. After a midline abdominal incision, both urethra were inserted into the catheter to quantify the volume of urine. The bladder was drained S, and a water-filled balloon catheter (attached to the tip of the emulsion penis sleeve storage tank attached to a PE-190 catheter) connected to an external pressure transducer was inserted through the bladder through a needle incision. Push the balloon catheter into the urethra and fasten it with a silk ligature. Confirm the correct position of the balloon by palpating the urine when the balloon is inflated and deflated. After the operation, the blood gas (by means of Nova stat summarized in Figure 3 blood gas decanter analysis) and pH were adjusted by adjusting the breathing rate, tidal volume, and / or positive-end expiratory pressure, Adjusted to within the normal definition. Intraurethral pressure is adjusted to an appropriate baseline (20-40 cm H20) by expanding and contracting the balloon. After a 30-minute stabilization period, the pigs were treated with Zhenta-adrenergic receptor (Zhenxinan; 10Θ micrograms / kg, iv), a non-selective avar 2_ adrenergic receptor antagonist [8 以 '(8 &amp; &amp; 12 钱, 13 抑)]-; ^-[3-[(5,8a, 9,10,11,12a, 13513a-octahydro-3-methoxy-6H isoquinoline 幷 [2, lg ] Gongdian [1,3] _12 (named H) · yl) -stonewindyl] propyl] -methylamine (for example, prepared by the procedure described in Clark et al., European patent application 524004 A1) Thus, for the compound according to the present invention, 300 μg / kg, iv), and ganglion antagonists (chloroisoammonium indolium ammonium; 200 μg / kg, iv, according to the procedure described in US Patent No. 3,025,294 Prepared) pre-treated. To determine urinary urinary response to blood pressure, a single phenylephrine was given (10 μg / kg). After the response returned to the baseline, the agonist was administered intravenously several times in increasing doses, and the maximum intraurethral and diastolic blood pressure response after each dose was recorded. The change in the dose interval from 5-120 minutes is to make the response -176- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page); · Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 517049 A7 —________ _ B7 V. Description of Invention (174) The Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics printed back to the baseline before giving the next dose 値. At the end of each experiment, pigs were sacrificed by lethal injection into pentobarbital. The maximal intra-urethral and diastolic blood pressure response of the standard and the representative compound of the present invention was measured. In this tiller, representative compounds of the present invention show activity. — ~~ I Blood pressure mode in vivo: Tamed female Yucatan mini pigs (12_35 kg; $ ί〇month old) to be able to rest quietly in the sling for one week during the surgical period. Use only pigs that can adapt to the sling. Surgery was performed on pigs under sterile conditions. A telemetry device (International Data Science Corporation, Sao Paulo, MN, UsA, model TAllPAD-70) was implanted into the cannula portion of the device inserted into the right lateral iliac artery and into the abdominal active gland. The device places the transmitter portion in a package created under the skin near the insertion point of the cannula. A vascular access port (Shns Deltec, São Paulo, mn, ', us A) with a silicon catheter was implanted for intravenous administration of the test compound. The catheter is inserted partially under the shoulder into the left or right jugular vein. A tensiometer converter (sf manufacturing company, Madison, WP U.S.A.) was sutured to the urinary tract and the wire was pulled out from the back. Allow pigs to recover for at least one week after surrender. On each experimental day, pigs were placed in a sling and allowed to stabilize before administration of phenylephrine stimulation (10 μg / kg, iv) to determine the needle position in the vascular access port, and to calibrate the telemeter and tension Meter probe. After the urethral tension and blood pressure return to baseline, a second non-cumulative curve for the test compound is established. The response to the test compound is expressed as the maximum percentage obtained by phenylephrine. In this analysis, representative compounds of the present invention showed activity. -177- This paper size applies Chinese National Standard (CNS) A4 specification (210X2 ^^) ~~ —- (Please read the precautions on the back before filling this page) 4 items. Fill in

1T 517049 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 Β7 i, Description of the Invention (175) Example 18 8: The points of loss of congestion and nasal congestion k Live European and foreign dogs were separated and the upper jaw was removed after analysis. Combine into standard Kreb, s solution. The nasal mucosa tissue was then removed from the surrounding tissue and cut into thin strips. Each strip was suspended under a static tension of 1 and suspended in a Kreb's solution having the following composition (mM). NaCl, il8.5; NaHC03, 25; dextrose, 5; KC1, 4.8; CaCl2 , 2,5; MgS04, 1.2, and JC2P04, 1.2. The Kreb's solution also contains cocaine (30 μM), corticosterone (30 μM), Xinxin'an (1 μM), indomethacin (10 μM), and ascorbic acid (100 μM). Broken neurons and external neurons absorption, beta-adrenergic receptors, prostanoid synthesis, and automatic oxidation of catecholamines. Each bath was maintained at 37 ° C and continuously aerated into μ% 〇2 / 5% CO2. The tissue strips were allowed to equilibrate for 1 hour, the tension was adjusted so that the resting tension was maintained at 1 g, and the tissue was washed with a Krebs solution every 0 minutes. The thin strips were then exposed to priming epinephrine (j 0 μM) by direct administration into the bath &apos;. The tissue is washed every 5 minutes for half an hour, or until the baseline tension is maintained at 1 gram per weave. Five minutes after the last wash, a cumulative concentration-action curve was established by directly administering phenylephrine to the bath. After the maximum response is obtained, the tissue is washed every 5 minutes for 30 minutes and every 15 minutes for the next hour. A second cumulative concentration-action curve was then established with phenylephrine (with or without citrus inhibitor) or the test compound. 2. In vivo dog nasal cavity force mode -178- This paper size applies to Chinese National Standard (CNS) Α4 size (210 × 297 mm) -------- 0 ^-(Please read the precautions on the back first Fill out this page again) Order 517049 A7 ------_ B7 V. Description of the invention (176) '~~ ~~ ---- (Please read the notes on the back before filling out this page) Male or female beagle ( 8-12 kg) fasted for 12-18 hours, and then anesthetized with pentobarbital sodium (33¾ g / kg, iv). The endotracheal tube of the endless belt was placed in the trachea, and the animals were mechanically ventilated with indoor air. The right femoral artery and vein were separated, and two polyethylene cannulae were inserted into the femoral vein. Use one of the cannulas to enter sodium pentobarbital (5 g / kg ^ h) through a perfusion pump to maintain anesthesia. The compound is administered using a second catheter, the tip of which is placed under the tip of the anesthesia cannula. An allogeneic cannula was inserted into the femoral artery and placed into the abdominal artery to measure arterial blood pressure and to draw blood samples for blood gas analysis. Use a remote sensing thermometer to detect body temperature. A water-filled balloon catheter connected to the external pressure transducer (by attaching the tip of the emulsion condom reservoir to the distal end of the cannula) was inserted into the nasal cavity approximately 2.5 deep through the right nostril. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Once the dog has been stabilized, a single amidine adrenaline stimulation (丨 μg / kg 'iv) is given to determine the nasal pressure and blood pressure response. At 5 to 30 minute intervals, amines were administered with adrenaline stimulation (0.01-10 μg / kg, iv). After 50-60 minutes, when the nasal pressure and blood pressure return to the baseline 値, the second curve (time control group) of phenylephrine is administered at an interval of 5.30 minutes or the test activator is administered. After the last dose, avar i- and / or avar 2_adrenergic receptor antagonist is administered to determine the receptor that mediates nasal pressure. Blood pressure, heart rate, ECG, and nasal pressure were measured through experiments using physiological maps. At the end of the study, it was killed by intravenous injection of an excess of sodium pentobarbital (5 ml, 389 mg / ml). Non-selective Avar ^ adrenergic receptor activator (phenylephrine), and -179- This paper size applies to Chinese National Standard (CNS) A4 (210 × 297 mm) 517049 A7 B7 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative. V. Description of the invention (177) Ava 1A-adrenergic receptor selective activator (amidoadrenaline) is active in both analyses and is used as a control group. In these analyses, representative compounds of the invention have shown activity. -180- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297mm) (Please read the note on the back J0-then fill and install-, write this page)

, 1T i #

Claims (1)

517049 Patent Application No. 087110098 Chinese Patent Application Amendment (July 91) Patent Application. Bulletin 1 · A compound represented by the formula: R4 A, kR5 where: A is ⑹N) m (Z) ( NR2) n; G or 1 respectively, the conditions are 4 () when q is 1, and m is 1 when 0 0; z is so2; η is 1; X is -NΗ-, _CH2- Or _〇CH2-; Y is 2-Weijun plin, 2-Junjun or 4-Weijun; R is fluorene, C1-6 alkyl or phenyl; R2, R3, R60 are each independently fluorene, Ci 6 alkyl; R4, R5: R6 and R7 are each independently hydrogen, Ci 6 alkyl, acryl 6 alkoxy, halogen, phenyl, C: 2 · 6 alkenyl, hydroxyl, wherein R 2, R 7 and phenyl may be Together form a pyridyl group, the substituent at the 3 position is halo, Ci6 alkyl or _ CN, provided that when R7 is hydroxyl, then when y is 2-imidazoline it is not -NH-; Or a pharmaceutically acceptable salt thereof. 2. The compound according to item i in the scope of the patent application, wherein eight of which are (feet 1 §〇21 ^ 112 ·) or (R3R6GNS02NR2-); or a pharmaceutically acceptable salt thereof, and Ri, R2, R3 and R60 are such as As defined in the first patent application scope. 517049 A8 B8 C8 Scope of patent application '--3 · According to the compound of scope 1 or 2 of the patent application scope, which is represented by the following formula: Among them: Xa4-NH-, -CH2- or -OCH2-; ·; k Y is 2-Mijunlin, 2-4 嗤 or 4-Mijun; R8 is Cu alkyl, phenyl or -NR14R15; R9 , R14 and R15 are each independently fluorene or Cualkyl;, R11, R12 and R13 are each independently hydrogen, Cu6 alkyl, Cw alkoxy, autogen, phenyl, C2-6 alkenyl or hydroxyl, wherein R9, R13 and Phenyl can jointly form indolyl, provided that when R13 is meridian, then X is not _NH- when γ is 2-imidazine, or a pharmaceutically acceptable salt thereof. The compound according to item 1 or 2 of the scope of patent application is represented by the following formula: Among them: This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). RU is Cm alkyl; R is H or C i. 6 .; R18, R19, R2. And R, are independently hydrogen, c "group, or a halide; K6 alkoxy or a pharmaceutically acceptable salt thereof. The compound according to item 丨 or 2 of the scope of patent application, which is represented by the following formula: NH-Yb RJ where:? 1) is 2-imidazoline; R is C 1.6 pit group; R34, R35 and R36 are each independently fluorene, CM, F, or Ci 6 alkyl · or a pharmaceutically acceptable salt thereof . 6. The compound according to item 1 or 2 of the scope of patent application, which is represented by the following formula Where: ¥ ° is 2-Mijun lin or 4-Mijun; R22 is CN6 alkyl; R23 is HSCu alkyl; 3- W049 A8 B8 C8 D8 1-6 alkoxy R24, R25, R25 and R27 are each independently hydrogen'Cl-6 alkyl, Ci group, halogen, phenyl, C2.6 alkyl or hydroxy; or a pharmaceutically acceptable salt thereof. The compound according to item 6 of the scope of patent application, which is represented by the formula: H CH2-Yc R: Wherein: 7 ° is 2-Munlin or 4-Miso; R is c 1.6 alkyl; R34, R35 and R36 are each independently fluorene, Cl, F, or c1-6 alkyl; or Its pharmaceutically acceptable salts. The compound according to item 1 or 2 of the patent application scope is represented by the following formula: Where: Yd is 2-imidazoline or 4-imidazole; R28 is Cle6 alkyl or phenyl; R29 is independently hydrogen or Cw alkyl; R30, R31, R32 and R33 are each independently hydrogen, Cl-6 alkyl, The size of plain or hydroxy paper is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 517049 A8 B8 C8 D8 6. The scope of patent application, or its pharmaceutically acceptable salts. 9. The compound according to item 8 of the scope of patent application, which is represented by the following formula: Wherein: Yd is 2-imidazoline or 4-imidazole; ^^ is an alkyl group; R34, R35, and R36 are each independently fluorene, Cl, F, or Cu alkyl; or a pharmaceutically acceptable salt thereof. 10 . According to the scope of the patent application for the 1 or 2 compounds, which is represented by the following formula: R55. Must R5 &quot; 7 Where =, -CH2- or -OCH2-; Yg is 2-imidazoline, 2-oxazoline or 4-imidazole; ^^ is "alkyl"; R56 forms unsubstituted or optionally substituted 5-or Part of a 6-membered ring, where the optional substituent on the ring is halogen, CN6 alkyl, or -CN, and this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 丄 7049 R56 is (CH2) k, where k is 2 or 3, and is CH = CH, CH = CHCH2, or CH2CH = CH; R57, R58, and R59 are each independently hydrogen, C16 alkyl, -CF3, C16 alkoxy, Halogen, phenyl, C2-6 alkenyl or hydroxyl; or a pharmaceutically acceptable salt thereof. 1 1 · The compound according to item 1 or 2 of the scope of patent application, which is represented by the following formula: Equipment Among them: X, -NH-, -CH2- or -〇CH2-; Ya is the olfactory 2-17; R is the pit base of C1.6; R49 is only OR. "Alkyl; R50, R51, R52, and R53 are each independently hydrogen, alkynyl, carbamoyl, self-priming, acyl, C6-6-yl or mesyl" Among them, R49, R53 and phenyl may together form an indolyl group; or a pharmaceutically acceptable salt thereof. It is represented by the following formula: 12. Compound according to item 1 or 2 of the scope of patent application -6- Wherein:, _CH2- or -〇ch2-; Y6 is 2-imidazoline, 2-oxazoline or 4-imidazole; R41, R42 and R43 are each independently H4C16 morpho; R44, R45, R46 and R47 are each independent Are hydrogen, Ci 6 alkyl, C &quot; alkoxy, halogen, phenyl, C2.6 fluorenyl, and hydroxyl, wherein R42 'R47 and phenyl can together form an indolyl; or a pharmaceutically acceptable salt thereof . 13. The compound according to item 1 or 2 of the scope of patent application, which is selected from: (N- [3- (4,5-dihydro-15--imidazol-2-ylmethoxy) -phenyl] methanesulfonate Fluorenamine); (N- [6-chloro-3- (4,5-dihydro-1H-imidazol-2-ylmethoxy) -2-methyl-phenyl] formamidine); (N_ [6-Bromo-3- (4,5-dihydro_1H-imidazol-2-ylmethoxy) -2-methyl-phenyl] methanesulfonamide); Ν- [5 · (4,5 -Dihydro-1H-imidazol-2-ylmethoxy) -2-fluoro-phenyl] methanesulfonamide; N- [3- (4,5-dihydro · 1Η-imidazol-2-ylfluorenyl oxide) Yl) -2-fluorenyl-phenyl] sulfenylsulfonamide; N- [3- (imidazolidin-2-ylamino) -2-methyl-phenyl] methanesulfonamide; N- [5 -(4,5-dihydro-1H-imidazol-2-ylmethyl) -2-methyl-phenyl] methanesulfonamide; N- [2-fluoro-5- (1 H-imidazole-4 ( 5) -ylmethoxy) -phenyl] methanesulfonamide; N, N-dimethyl-N,-[3- (4,5-dihydro-1H-imidazol-2-yl) hydrochloride (Oxy) -phenyl] sulfofluorenediamine; -7- this paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 517049 A8 B8 C8 patent application scope (3-chloro-1-methylsulfonyl -1H-pyridin-6-yl) -imidazolidinyl-amine; or a pharmaceutically acceptable salt thereof . 14. A method for preparing a compound according to item 1 or 2 of the scope of patent application, and a pharmaceutically acceptable salt thereof, wherein: a) A is Risc ^ NH ·, or -0CH2-, and Y is 2-imidazoline Or 'R R4 React with 1,2-diaminoethane, wherein R1, R4, r5, r6 and R7 are as defined in item 1 of the scope of patent application; or b) A is RisC ^ NH- and X is -CH2-, And Y is a 4 mic bite, the method includes a compound of the formula: React with ammonia, where R1, R, r5, Rm are as defined in the first patent application scope; or c) A is Rhc ^ NH-, X is -CH2- or -〇CH2 ... and γ is 4 imidazole , The method includes adding a compound of the formula: S02N (CH3) 2 ^ TBDMS R4 R5 χ— &lt; ΝΊί The paper size is applicable to China National Standard (CNS) A4 (210 x 297 public love) The application for a patent is to react an alkylsulfone functional compound with a base under a blunt agent, and the protective group should be removed. Its + R1, R4, R5, R1 ^^ = range No. 1 shot, please apply for patent d), A is Rls〇2NH-, χ i〇CH2, and γ is a deductive taste. The method includes a compound of the formula: React with dilute inorganic acids such as hydrochloric acid in an inert organic solvent such as nitrile, and R, R4, R5, R6 and R7 are as defined in item i of the patent scope; or e) A is RisC ^ NH -, Where X is -NH- and γ is 2-imidazoline, then the method includes a compound of the formula: ' Reacts with 2-chloroimidazoline, where Ri, r4, r5, R6 and R7 are as defined in the main patent scope item 1; or f) R2 and R7 can jointly form an alkylene or 5_ or 6-membered A radical with 2 s 3 carbon atoms in the ring, the method includes a compound of the following formula: Soil-9-This paper is a national standard (CNS) A4 specification (210X297 public director) 517049 8 8 8 8 A BCD application patent scope S02fV V0-R4 ^ \ ^ CH2CNl L II V% 5 reaction to convert cyano to fluorenimide functionality, which is formed by condensation with 1,2-diaminoethane 2-imidazolinyl, where R1, R4, R5, and R6 are as defined in the first patent application range, and R50 is (CH2) K where k is 2 or 3, CH = CH, CH = CHCH2, or CH2CH = CH; or g) where X is -NH- and Y is 2-imidazoline, the method includes a compound of formula: Reaction with 2-haloimidazoline to directly produce the desired compound, wherein R1, R4, R5, and R6 are as defined in item 1 of the scope of patent application; or h) X is -OCH2-, and Y is 2- For imidazolines, the method includes a compound of the formula: It reacts with ethanol and gaseous hydrochloric acid in dichloromethane to form a monoimide, which is then condensed with 1,2-diaminoethane to form 2-imidazolinyl -10 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297mm). 6. The scope of patent application ^ R, R, r5, &amp; r6 is the method as specified in the first patent scope of the Chinese patent application. I) X is -NH- 'and Y is 2 ^ zoline or thiazoline, which includes a compound of formula: 〇II NHCNH (CH2) 2CH2CI Ϊ R5, or the water-soluble compounds of the above compounds, R6 and R7 are heated in the reaction solution of potassium fluoride and alumina in acetonitrile as claimed in the patent application, where R1, R4, and r5 surround the first Or j) where A is ris〇2nh-, X is or -0CIi2 ... and γ is 2 imidazoline, then the method includes a compound of the formula: H R4 Reacts with ethylenediamine and trifluorenyl aluminum, where R1, R4, R5, r6 &amp; r7 are as defined in item 1 of the scope of patent application. 1 5 · — compounds, R7 H R4 NH Y OC2H5 R5 -11-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 517049 A8 B8 8 8 8 8 A BCD 517049 6. Application scope 19. A compound, Among them, R1, R4, R5, R6 and R7 are as defined in item 1 of the scope of patent application. 20. a compound, Among them, R1, R4, R5 and R6 are as defined in item 1 of the scope of patent application. 2 1 · — compounds, nh2 Rs where R1, R4, R5, and R6 are as defined in item 1 of the scope of patent application. -13- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 517049 22. a compound S〇2R1 r4 I And R6 are as specified in item i of the scope of patent application, among which Ri, R4, R5 2 3 · — compounds, 〇 II NHCNH (CH2) 2ch2C! R5 where R, R, R5, R6 and R7 are defined as the item in the scope of patent application]. 24 · — compounds, H R4 Where X is -CH2-or _0CH2-, and Ri, r4, r5, ruler 6 and Han 7 are shallow as defined in the scope of patent application_1. ^ σ -14-^ 1/049 A8 B8 η——g8s, patent application ϋ '-mg • Compounds according to item 1 or 2 of the scope of patent application, which are medically active substances. 26. The compound according to item g or 2 of the application patent, which is used for the preparation of prevention and / or treatment of disease states that can be slowed by treatment with avar 1a / il adrenergic receptor activator Pharmaceutical products. • A pharmaceutical composition for treating and / or preventing a disease state that can be alleviated by treatment with avalia / il adrenergic receptor activator, comprising a therapeutically effective amount according to the first patent application scope A compound according to any one of to 13 in combination with a therapeutically inert carrier. 28 'A compound according to item 1 or 2 of the scope of patent application, which is used to manufacture pharmaceuticals ° ° 29. A compound according to item 1 or 2 of the scope of patent application, which is used to manufacture compounds for the prevention and / or treatment of urinary incontinence, nose Department of congestion, abnormal erections, depression, focal depression, /, dementia, aging, Alzheimer's disease, lack of attention and discrimination, and / or eating disorders. 30. A compound according to item 1 or 2 of the scope of patent application can be obtained by a method according to item 14 of the scope of patent application. -15-